Diphenylmethane protective agent

ABSTRACT

An object of the present invention is to develop a protecting group, which can prevent solidification or insolubilization of a compound by protecting a functional group to achieve easy separation and purification after a reaction. 
     A diphenylmethane compound represented by general formula (1): 
     
       
         
         
             
             
         
       
         
         
           
             wherein Y represents —OR 19  (wherein R 19  represents a hydrogen atom or an active ester-type protecting group), —NHR 20  (wherein R 20  represents, for example, a hydrogen atom, a C 1-6  linear or branched alkyl group, or an aralkyl group, at least one of R 1  to R 10  represents a group represented by formula (2):
 
—O—R 11 —X-A  (2)
 
             and the others each independently represent a hydrogen atom, a halogen atom, a C 1-4  alkyl group, or a C 1-4  alkoxy group; R 11  represents a C 1-16  linear or branched alkylene group; X represents O or CONR 21  (wherein R 21  represents a hydrogen atom, or a C 1-4  alkyl group; and A represents, for example, a group represented by formula (3).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 16/307,105, filed on Dec. 4, 2018, which is a national stage entryof International Application PCT/JP2017/022525, filed on Jun. 19, 2017,and claims foreign priority from Japanese Patent Application No.2016-219631, filed on Nov. 10, 2016, and Japanese Patent Application No.2016-121986, filed on Jun. 20, 2016, the entire contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a novel diphenylmethane compound usefulas a protective agent for a carboxy group, a hydroxy group, a diolgroup, an amino group, an amide group, and a mercapto group.

BACKGROUND OF THE INVENTION

In synthesis of peptides or various compounds, protection of functionalgroups such as a carboxy group, a hydroxy group, a diol group, an aminogroup, an amide group, and a mercapto group may be required for carryingout the reaction. Desirable protecting groups for the protection includethose, which can protect functional groups by an easy process and beeliminated under moderate conditions. For example, benzyl esters (Bn)and tert-butyl ester are known as carboxy protecting groups. Recently,it is reported that benzyl alcohol-based compounds anddiphenylmethane-based compounds are useful as protecting groups (PatentLiteratures 1 and 2).

CITATION LIST Patent Literatures

Patent Literature 1: WO 2012/029794 A

Patent Literature 2: WO 2010/113939 A

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

However, there is a drawback that a compound in which a functional groupis protected with a conventional protecting group can easily beprecipitated. Specifically, in peptide synthesis, since such a compoundbecomes insoluble in even an organic solvent, separation andpurification of the compound after the reaction often become difficult.These difficulties in separation and purification are serious problemsin peptide synthesis in which condensation reactions are carried outsuccessively.

Accordingly, an object of the present invention is to provide aprotective agent, which protects a functional group of a compound, whichleads to dissolution of the compound in an organic solvent withoutsolidification or insolubilization, which allows easy separation andpurification of the compound after a reaction.

Means for Solving the Problem

The present inventors have made investigations on various substituentsof a diphenylmethane compound, which results in development of acompound having a trialkylsilyloxy substituent at the end of anoxyalkylene group by which the substituent is connected to a benzenering of a diphenylmethane compound. The present inventors have foundthat a compound in which a functional group is protected with the abovediphenylmethane compound is hardly precipitated in an organic solventand easily separated and purified by a liquid-liquid phase separationoperation, and thus the compound is useful as a protective agent, andconsequently have made the present invention.

That is, the present invention provides the following [1] to [9].

[1] A diphenylmethane compound represented by general formula (1):

wherein Y represents —OR¹⁹ (wherein R¹⁹ represents a hydrogen atom or anactive ester-type protecting group), —NHR²⁰ (wherein R²⁰ represents ahydrogen atom, a C₁₋₆ linear or branched alkyl group, or an aralkylgroup), an azide, a halogen atom, an oxime combined with a methylenegroup, or a carbonyl group combined with a methylene group, and at leastone of R¹ to R¹⁰ represents a group represented by formula (2):—O—R¹¹—X-A  (2)

and the others each independently represent a hydrogen atom, a halogenatom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxy group; R¹¹ represents a C₁₋₁₆linear or branched alkylene group; X represents O or CONR²¹ (wherein R²¹represents a hydrogen atom or a C₁₋₄ alkyl group); and A represents agroup represented by formula (3), (4), (5), (6), (7), (8), (9), (10),(11), (12), or (13):

wherein R¹², R¹³, and R¹ may be the same or different and eachindependently represent a C₁₋₄ linear or branched alkyl group or anoptionally substituted aryl group; R¹⁵ represents a single bond or aC₁₋₃ linear or branched alkylene group, and R¹⁶, R¹⁷, and R¹⁸ eachindependently represent a C₁₋₃ linear or branched alkylene group.

[2] The diphenylmethane compound according to [1], wherein Y is —OR¹⁹(wherein R¹⁹ represents a hydrogen atom), —NHR²⁰ (wherein R²⁰ representsa hydrogen atom, a C₁₋₆ linear or branched alkyl group, or an aralkylgroup), an azide, a halogen atom, an oxime combined with a methylenegroup, or a carbonyl group combined with a methylene group.

[3] The diphenylmethane compound according to [1], wherein Y is —OR¹⁹(wherein R¹ represents a hydrogen atom or an active ester-typeprotecting group), —NHR²⁰ (wherein R²⁰ represents a hydrogen atom, aC₁₋₆ linear or branched alkyl group, or an aralkyl group), an azide, ahalogen atom, or an oxime combined with a methylene group.

[4] The diphenylmethane compound according to [1], wherein Y is —OR¹⁹(wherein R¹ represents a hydrogen atom), —NHR²⁰ (wherein R²⁰ representsa hydrogen atom, a C₁₋₆ linear or branched alkyl group, or an aralkylgroup), an azide, a halogen atom, or an oxime combined with a methylenegroup.

[5] The diphenylmethane compound according to any one of [1] to [4],wherein at least one of R¹ to R⁵ and at least one of R⁶ to R¹⁰ are eachindependently a group represented by formula (2) and the others are eachindependently a hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxygroup.

[6] The diphenylmethane compound according to any one of [1] to [5],wherein R¹¹ is a C₁₋₆ linear or branched alkylene group.

[7] The diphenylmethane compound according to any one of [1] to [6],wherein R¹¹ is a C₆₋₁₆ linear or branched alkylene group.

[8] The diphenylmethane compound according to any one of [1] to [7],wherein R¹⁵ is a single bond or a methylene group, and R¹⁶, R¹⁷, and R¹⁸are each independently a methylene group.

[9] A protective agent for a carboxy group, a hydroxy group, a diolgroup, an amino group, an amide group, or a mercapto group, comprising adiphenylmethane compound according to any one of [1] to [8].

Effects of Invention

A compound in which a functional group is protected by a diphenylmethanecompound (1) of the present invention readily becomes liquid and has anincreased solubility in a solvent, which leads to easy separation andpurification after a condensation reaction.

If insolubilization or solidification of a raw materials or anintermediate is an obstacle in a process of producing various chemicalssuch as medicines and agrochemicals, such problems can be solved bybonding the diphenylmethane compound (1) of the present invention to theraw materials or the intermediate compounds to increase liquidity andsolubility thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of measurement of solubility in cyclopentylmethyl ether (CPME).

DESCRIPTION OF THE EMBODIMENTS

A diphenylmethane compound of the present invention represented bygeneral formula (1) is characterized in that at least one of R¹ to R¹⁰has a structure represented by formula (2). Such a structure facilitatesliquefaction of a compound protected with the diphenylmethane compound(1) and significantly increases solubility in a solvent.

In general formula (1), Y represents —OR¹⁹ (wherein R¹⁹ represents ahydrogen atom or an active ester-type protecting group), —NHR²⁰ (whereinR²⁰ represents a hydrogen atom, a C₁₋₆ linear or branched alkyl group,or an aralkyl group), an azide, a halogen atom, an oxime combined with amethylene group, or a carbonyl group combined with a methylene group.Examples of the halogen atom include a fluorine atom, a bromine atom, achlorine atom, and an iodine atom. The carbonyl group combined with amethylene group is useful as a protecting group for an amino group.

Examples of the active ester-type protecting group include an activeester-type carbonyl group and an active ester-type sulfonyl group.Examples of the active ester-type carbonyl group include a carbonyloxysuccinimide, an alkoxycarbonyl group, an aryloxycarbonyl group, and anaralkyloxy carbonyl group, and more preferred is, for example, acarbonyloxy succinimide.

Examples of the active ester-type sulfonyl group include analkylsulfonyl group and an arylsulfonyl group, and more preferred are,for example, a C₁-C₆ alkylsulfonyl group and a p-toluenesulfonyl group.

Y is preferably —OR¹⁹ (wherein R¹⁹ represents a hydrogen atom), —NHR²⁰(wherein R²⁰ represents a hydrogen atom, a C₁₋₆ linear or branched alkylgroup, or an aralkyl group), or a halogen atom.

The diphenylmethane compound of the present invention refers to a groupin which at least one of R¹ to R¹⁰ is represented by formula (2). Interalia, in view of solubility of a protecting group-introduced compoundand removal of the protecting group, preferred is a group in which 1 to4 of R¹ to R¹⁰ are represented by formula (2), more preferred is a groupin which 2 to 4 of R¹ to R¹⁰ are represented by formula (2), and evenmore preferred is a group in which 2 to 3 of R¹ to R¹⁰ are representedby formula (2). Still more preferred is a group in which at least one ofR¹ to R⁵ and at least one of R⁶ to R²⁰ are each independently a grouprepresented by formula (2).

The others are each independently a hydrogen atom, a halogen atom, aC₁₋₄ alkyl group, or a C₁₋₄ alkoxy group. Examples of the other halogenatoms represented by R¹ to R¹⁰ include a fluorine atom, a chlorine atom,and a bromine atom. Inter alia, preferred is a chlorine atom. Examplesof the other C₁₋₄ alkoxy group include a methoxy group, an ethoxy group,an n-propyloxy group, an isopropyloxy group, and an n-butyloxy group.Inter alia, preferred are a methoxy group and an ethoxy group. Examplesof the C₁₋₄ alkyl group include a methyl group, an ethyl group, ann-propyl group, an isopropyl group, and an n-butyl group. Inter alia,preferred are a methyl group and an ethyl group.

R¹¹ represents a C₁₋₁₆ linear or branched alkylene group. The alkylenegroup is preferably a C₂₋₁₆ linear or branched alkylene group, morepreferably a C₄₋₁₆ linear or branched alkylene group, even morepreferably a C₆₋₁₆ linear or branched alkylene group, and still morepreferably a C₈₋₁₄ linear or branched alkylene group. Specific examplesof the alkylene group include a methylene group, an ethylene group, atrimethylene group, a tetramethylene group, a pentamethylene group, ahexamethylene group, a heptamethylene group, an octamethylene group, anonamethylene group, a decamethylene group, an undecamethylene group, adodecamethylene group, and a tetradecamethylene group.

X represents 0 or CONR²¹.

Herein, R²¹ represents a hydrogen atom or a C₁₋₄ alkyl group, and ispreferably a hydrogen atom.

The letter A represents a group represented by formula (3), (4), (5),(6), (7), (8), (9), (10), (11), (12), or (13). R¹², R¹³, and R¹⁴ may bethe same or different and each independently represent a C₁₋₆ linear orbranched alkyl group or an optionally substituted aryl group. Herein,examples of the C₁₋₆ alkyl group include a methyl group, an ethyl group,an n-propyl group, an isopropyl group, an n-butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, an n-pentyl group, and ann-hexyl group. Inter alia, preferred is a C₁₋₄ alkyl group, and morepreferred are a methyl group, tert-butyl, and an isopropyl group.

Examples of the optionally substituted aryl group include a C₆₋₁₀ arylgroup. Specific examples include a phenyl group and a naphthyl group,each optionally substituted with a C₁₋₃ alkyl group. Inter alia, morepreferred is a phenyl group.

R¹⁵ represents a single bond or a C₁₋₃ linear or branched alkylenegroup. Examples of the C₁₋₃ linear or branched alkylene group include amethylene group, an ethylene group, a trimethylene group, and apropylene group. Inter alia, preferred is a single bond.

R¹⁶, R¹⁷, and R¹⁸ each independently represent a C₁₋₃ linear or branchedalkylene group. Examples of the C₁₋₃ linear or branched alkylene groupinclude a methylene group, an ethylene group, a trimethylene group, anda propylene group. Inter alia, preferred is a methylene group.

More preferred is a compound represented by general formula (1) in whichY is —OR¹⁹ (wherein R¹⁹ represents a hydrogen atom), —NHR²⁰ (wherein R²⁰represents a hydrogen atom, a C₁₋₆ linear or branched alkyl group, or anaralkyl group), or a halogen atom; at least one, and preferably 1 to 3,of R¹ to R⁵ is a group represented by formula (2), at least one, andpreferably 1 to 3, of R⁶ to R¹⁰ is a group represented by formula (2),and the others are each independently a hydrogen atom, a C₁₋₄ alkylgroup or a C₁₋₄ alkoxy group; R¹¹ is a C₂₋₁₆ linear or branched alkylenegroup; R¹⁵ is a single bond or a methylene group; and R¹⁶, R¹⁷, and R¹⁸are each independently a methylene group.

More preferred is a compound represented by general formula (1) in whichR¹¹ is a C₆₋₁₆ linear or branched alkyl group; X is O or CONH; A is agroup represented by formula (3) or (13); R¹², R¹³, and R¹⁴ are the sameor different and each independently represent a C₁₋₄ alkyl group; R¹⁵ isa single bond; and R¹⁶, R¹⁷, and R¹⁸ are each independently a methylenegroup.

Herein, specific examples of those to which a group represented byformula (2) is bonded are shown below.

wherein R^(3b) and R^(8b) each independently represent a hydrogen atom,a C₁₋₄ alkyl group, or a C₁₋₄ alkoxy group, and Y, A, X, and R¹¹ are thesame as defined above.

Specific examples of the diphenylmethane compound (1) of the presentinvention include the following (a) to (e). In (a) to (e), Y represents—OR¹⁹ (wherein R¹⁹ represents a hydrogen atom), —NHR²⁰ (wherein R²⁰represents a hydrogen atom, a C₁₋₆ linear or branched alkyl group, or anaralkyl group), or a halogen atom.

(a) TIPS2-Type-PP Protective Agent

Herein, R^(a) represents a hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄alkoxy group.

(b) TIPS2-Type-OO Protective Agent

Herein, R^(a) represents a hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄alkoxy group.

(c) TIPS3-Type-OPP Protective Agent

Herein, R^(a) represents a hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄alkoxy group.

(c) TIPS4-Type-PP Protective Agent

Herein, R^(a) represents a hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄alkoxy group.

(d) TIPS6-Type-PP Protective Agent

Herein, R^(a) represents a hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄alkoxy group.

(e) TIPS9-Type-OPP Protective Agent

Herein, R^(a) represents a hydrogen atom, a C₁₋₁₄ alkyl group, or a C₁₋₄alkoxy group.

(e) TBDPS2-Type-PP Protective Agent

Herein, R^(a) represents a hydrogen atom, a C₁₋₁₄ alkyl group, or a C₁₋₄alkoxy group.

The diphenylmethane compound (1) of the present invention can beproduced, for example, according to the following reaction scheme.

Herein, Hal represents a halogen atom, at least one of R^(1a) to R^(10a)represents a hydroxy group and the others each independently represent ahydrogen atom, a halogen atom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxygroup, B represents an amino acid having a mercapto group or an aminoacid derivative having a mercapto group, Z represents a compound havinga —CONH-group, and R¹ to R¹⁰, R²⁰, X, and A are the same as definedabove.

A silyloxylated alkyl halide (14) is reacted with a diphenylketone (15)to give a silyloxy diphenylketone (16), subsequently the ketone group isconverted to a hydroxy group followed by azidation to give an azidecompound (18), and then the azido group is subjected to Staudingerreaction to afford a diphenylmethane compound (1b). A diphenylmethanecompound (1a) having a hydroxy group is reacted with a compound having a—CONH₂ group to afford a compound (17). A diphenylmethane compound (1a)having a hydroxy group is halogenated to give a diphenylmethane compound(1c) having a halogen atom followed by reaction with an aminerepresented by R²⁰—NH₂ to afford a compound (1f). A diphenylmethanecompound (1a) having a hydroxy group is reacted with an amino acidhaving a mercapto group or an amino acid derivative having a mercaptogroup to afford a compound (1d). A ketone compound (16) is oximated toafford an oxime compound (1e).

A silyloxylated alkyl halide (14) as a raw material can be produced by,for example, reacting a halogenated alcohol with a silylation agent inthe presence of a base. Examples of the halogen atom in formula (14)include a bromine atom.

Examples of the silylation agent used in the above reaction includetriisopropylsilyl chloride (TIPSCl), triisopropylsilyl bromide,triisopropylsilyl iodide, methanesulfonyl triisopropylsilyl,trifluoromethanesulfonyl isopropylsilyl, p-toluenesulfonyltriisopropylsilyl, tert-butylchlorodiphenylsilane (TBDPSCl), andtert-butyldimethylchlorosilane (TBSCl).

Examples of the base include organic bases such as TEA, DIPEA, DBU,diazabicyclononene (DBN), DABCO, imidazole, N-methyl imidazole,N,N-dimethyl aniline, pyridine, 2,6-lutidine, DMAP, LDA, NaOAc, MeONa,MeOK, lithium hexamethyldisilazide (LHMDS), and sodiumbis(trimethylsilyl)amide (NaHMDS); and inorganic bases such as Na₂CO₃,NaHCO₃, NaH, NaNH₂, K₂CO₃, and Cs₂CO₃.

Examples of the solvent include hydrocarbons such as hexane and heptane;ethers such as diethyl ether, diisopropyl ether, cyclopentyl methylether (CPME), tetrahydrofuran, and dioxane; nitriles such asacetonitrile; amides such as dimethylformamide (DMF), dimethylacetamide,and hexamethylphosphoramide; sulfoxides such as dimethylsulfoxide;lactams such as N-methylpyrrolidone; halogenated hydrocarbons, such aschloroform and dichloromethane; and aromatic hydrocarbons such astoluene and xylene; or a mixed solvent thereof.

The reaction may be carried out, for example, at 0° C. to 100° C. for 1to 24 hours.

The reaction between the silyloxylated alkyl halide (14) and thediphenylketones (15) is preferably carried out in the presence of abase.

Examples of the base used in the above reaction include organic basessuch as TEA, DIPEA, DBU, DBN, DABCO, imidazole, N-methyl imidazole,N,N-dimethyl aniline, pyridine, 2,6-lutidine, DMAP, LDA, NaOAc, MeONa,MeOK, lithium hexamethyldisilazide (LHMDS), and sodiumbis(trimethylsilyl)amide (NaHMDS); and inorganic bases such as Na₂CO₃,NaHCO₃, NaH, K₂CO₃, and Cs₂CO₃.

Examples of the solvent include hydrocarbons such as hexane and heptane;ethers such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran,and dioxane; nitriles such as acetonitrile; amides such as DMF,dimethylacetamide, and hexamethylphosphoramide; sulfoxides such asdimethylsulfoxide; lactams such as N-methylpyrrolidone; halogenatedhydrocarbons, such as chloroform and dichloromethane; and aromatichydrocarbons such as toluene and xylene; or a mixed solvent thereof.

The reaction may be carried out, for example, at 40° C. to 150° C. for 1to 24 hours.

Examples of the method for converting a ketone group of the compound offormula (16) to a hydroxy group include a process comprising reductionusing a reducing agent.

Examples of the reducing agent include lithium borohydride, sodiumborohydride, aluminum lithium hydride, and aluminum hydride. Examples ofthe solvent include hydrocarbons such as hexane and heptane; alcoholssuch as methanol and ethanol; ethers such as diethyl ether, diisopropylether, CPME, tetrahydrofuran, and dioxane; and aromatic hydrocarbonssuch as toluene and xylene; or a mixed solvent thereof. The reaction ispreferably carried out, for example, at 0° C. to 90° C. for 1 to 24hours.

The method for azidation of the hydroxy group in formula (1a) ispreferably a method comprising reacting with diphenylphosphoryl azide orbis(p-nitrophenyl)phosphoryl azide in the presence of a base.

Examples of the base include organic bases such as DBU, DBN, TEA, DIPEA,and DABCO. Examples of the solvent include hydrocarbons such as hexaneand heptane; ethers such as diethyl ether, diisopropyl ether, CPME,tetrahydrofuran, and dioxane; and aromatic hydrocarbons such as tolueneand xylene; or a mixed solvent thereof. The reaction may be carried out,for example, at 0° C. to 100° C. for 0.5 to 144 hours.

Examples of the method for reducing the azide compound (18) to the aminecompound (1b) include Staudinger reaction comprising reacting withtriphenylphosphine in the presence of water or a catalytic reduction.Inter alia, preferred is the Staudinger reaction.

Examples of the solvent for the Staudinger reaction include hydrocarbonssuch as hexane and heptane; ethers such as diethyl ether, diisopropylether, CPME, tetrahydrofuran, and dioxane; and aromatic hydrocarbonssuch as toluene and xylene; or a mixed solvent thereof. The reaction maybe carried out, for example, at 20° C. to 100° C. for 1 to 24 hours.

The reaction between the compound of formula (1a) and the compoundhaving a —CONH₂ group is preferably a method comprising reacting withthe compound having a —CONH₂ group in the presence of an acid catalyst.

Examples of the compound having a —CONH₂ group or a —OCONH₂ groupinclude Fmoc-NH₂, ethyl carbamate, isopropyl carbamate, AcNH₂, HCONH₂,Cbz-NH₂, CF₃CONH₂, and Fmoc-amino acid-NH₂. Examples of the acidcatalyst include acids such as trifluoromethanesulfonic acid,methanesulfonic acid, p-toluene sulfonic acid, acetic acid, hydrochloricacid, and sulfuric acid. Examples of the solvent include hydrocarbonssuch as hexane and heptane; ethers such as diethyl ether, diisopropylether, CPME, tetrahydrofuran, and dioxane; aromatic hydrocarbons such astoluene and xylene; and halogenated hydrocarbons, such as chloroform anddichloromethane; or a mixed solvent thereof. The reaction may be carriedout, for example, at 20° C. to 150° C. for 0.5 to 48 hours.

The compound of formula (1c) can be produced from the compound offormula (1a) by reacting with a halogenating agent in the presence of abase. Examples of the halogen atom in formula (1c) include a chlorineatom.

Examples of the halogenating agent include thionyl chloride, acetylchloride, acetyl bromide, triphenylphosphine/carbon tetrachloride, andtriphenylphosphine/carbon tetrachloride.

Examples of the base include organic bases such as pyridine, TEA, DBU,DBN, DIPEA, and DABCO.

Examples of the solvent include hydrocarbons such as hexane and heptane;ethers such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran,and dioxane; aromatic hydrocarbons such as toluene and xylene;halogenated hydrocarbons, such as chloroform and dichloromethane; anddimethylformamide (DMF); or a mixed solvent thereof. The reaction may becarried out, for example, at 0° C. to 100° C. for 0.5 to 24 hours.

The reaction between the compound of formula (1a) and the amino acidderivative having a mercapto group is preferably a method comprisingreacting with an amino acid having a mercapto group or an amino acidderivative having a mercapto group in the presence of an acid catalyst.

Examples of the amino acid having a mercapto group include cysteine,homocysteine, mercaptonorvaline, and mercaptonorleucine. Examples of theamino acid derivative having a mercapto group include the above aminoacids in which N terminals of the compounds are N-methylated; the aboveamino acids in which N terminals of the compounds are each protectedwith, for example, a benzyloxycarbonyl (Cbz or Z) group, afluorenylmethoxycarbony (Fmoc) group, an acetyl (Ac) group, a benzylgroup, an allyl group, an allyloxycarbonyl (Aloc) group, a2-nitrobenzenesulfonyl (Ns) group, a 2,4-dinitrobenzenesulfonyl (DNs)group, and a 4-nitrobenzenesulfonyl (Nos) group; the above amino acidsin which C terminals of the compounds are each protected with, forexample, an amide group, a methyl ester group, an ethyl ester group, atert-butyl ester group, a benzyl ester group, and an allyl ester group;the above amino acids in which both N terminals and C terminals are eachprotected with the above protecting groups; and D-amino acid compoundscorresponding to the above compounds.

Examples of the acid catalyst include acids such astrifluoromethanesulfonic acid, methanesulfonic acid, p-toluene sulfonicacid, acetic acid, hydrochloric acid, and sulfuric acid. Examples of thesolvent include hydrocarbons such as hexane and heptane; ethers such asdiethyl ether, diisopropyl ether, CPME, tetrahydrofuran, and dioxane;aromatic hydrocarbons such as toluene and xylene; and halogenatedhydrocarbons, such as chloroform and dichloromethane; or a mixed solventthereof. The reaction may be carried out, for example, at 20° C. to 150°C. for 0.5 to 24 hours.

The compound of formula (1f) can be produced from the compound offormula (1c) by reacting with an amine represented by R²⁰—NH₂ in thepresence of a base.

Examples of the base include tertiary amines such as diisopropyl amineand triethyl amine. Examples of the solvent include hydrocarbons such ashexane and heptane; ethers such as diethyl ether, diisopropyl ether,CPME, tetrahydrofuran, and dioxane; aromatic hydrocarbons such astoluene and xylene; and halogenated hydrocarbons, such as chloroform anddichloromethane; or a mixed solvent thereof. The reaction may be carriedout, for example, at 0° C. to 100° C. for 0.5 to 24 hours.

The compound of formula (1e) can be produced from the compound offormula (16) by reacting the ketone group in formula (16) with an acidaddition salt of a hydroxylamine in the presence of a base. Examples ofthe salt adduct of the hydroxylamine include a hydrochloride, asulfates, an acetate, a trifluoroacetate, a methanesulfonate, atrifluoromethanesulfonate, and a p-toluenesulfonate.

Examples of the base include organic bases such as TEA, pyridine, DIPEA,N,N-dimethyl aniline, DBU, DBN, and DABCO; and inorganic bases such assodium hydroxide, sodium hydrogencarbonate, potassium hydroxide, andpotassium carbonate.

Examples of the solvent include hydrocarbons such as hexane and heptane;ethers such as diethyl ether, diisopropyl ether, cyclopentyl methylether (CPME), tetrahydrofuran, and dioxane; halogenated hydrocarbons,such as chloroform and dichloromethane; and aromatic hydrocarbons suchas toluene, xylene; or a mixed solvent thereof. The reaction may becarried out, for example, at 20° C. to 120° C. for 1 to 96 hours.

The diphenylmethane compound (1) of the present invention can be used asa protective agent for a functional group such as a carboxy group, ahydroxy group, a diol group, an amino group, an amide group, or amercapto group. A compound in which a carboxy group, a hydroxy group, adiol group, an amino group, an amide group, or a mercapto group isprotected with the diphenylmethane compound (1) of the present inventionis characterized by increased liquidity and solubility in a solvent.Thus, a compound in which a functional group is protected with thediphenylmethane compound (1) of the present invention as a protectiveagent becomes liquid, and can be separated and purified by an operationsuch as liquid-liquid phase separation. In addition, a protecting groupobtained by using the inventive compound can be easily eliminated by anacid or catalytic reduction.

The compound, which can be protected, by the diphenylmethane compound(1) of the present invention may be a compound having a carboxy group, ahydroxy group, a diol group, an amino group, an amide group, or amercapto group. Examples include amino acids, peptides, saccharides,proteins, nucleotides, various medicinal compounds and agrochemicalcompounds, various polymers and dendrimers, and others.

Examples of a method for synthesizing peptides using the diphenylmethanecompound (1) of the present invention as a protective agent include amethod of production comprising the following steps (1) to (4).

(1) The diphenylmethane compound (1) of the present invention iscondensed with a C terminal carboxyl group of an N-protected amino acidor an N-protected peptide in a soluble solvent to give an N- andC-protected amino acid or an N- and C-protected peptide in which the Cterminal is protected with the diphenylmethane compound (1) of thepresent invention. Alternatively, the diphenylmethane compound (1) ofthe present invention is reacted with a C terminal amide group of anN-protected amino acid or an N-protected peptide in a soluble solvent togive an N- and C-protected amino acid or an N- and C-protected peptidein which the C terminal is protected with the diphenylmethane compound(1) of the present invention.

(2) The protecting group of the N terminal of the resulting N- andC-protected amino acid or N- and C-protected peptide is removed to givea C-protected amino acid or C-protected peptide.

(3) An N-protected amino acid or an N-protected peptide is condensedwith the N terminal of the resulting C-protected amino acid orC-protected peptide to give an N- and C-protected peptide.

(4) The protecting group of the N terminal and the protecting group ofthe C terminal of the resulting N- and C-protected peptide are removedto afford a desired peptide.

Examples

The present invention is described in more detail with reference toExamples below, but it should not be construed as being limited to theExamples in any way.

Example 1

Synthesis of TIPS2-Dpm-NH₂

(Hereinafter, Br—(CH₂)₁₁-OTIPS, TIPS2-Dpm-C═O, TIPS2-Dpm-OH,TIPS2-Dpm-N₃, and TIPS2-Dpm-NH₂ represent the respective structures inthe above scheme.)

(1) In 3.2 mL of DMF, 9.81 g of Br—(CH₂)₁₁-OTIPS (24.1 mmol), 2.29 g of4,4′-dihydroxybenzophenone (10.7 mmol), and 5.33 g of potassiumcarbonate (38.5 mmol) were suspended, and the suspension was heated to85° C. and stirred for 2 hours. The reaction solution was filtered, andthe residue was washed with 150 mL of heptane. The filtrate wassubjected to liquid-liquid extraction. To the resulting heptane layerwas added 71 mL of heptane, and the solution was washed by liquid-liquidextraction with 71 mL of DMF. The washing step by liquid-liquidextraction with heptane and DMF was repeated once more. To the resultingheptane layer was added 71 mL of heptane, and the solution was washed byliquid-liquid extraction as follows: once with 71 mL of 1 N hydrochloricacid, once with 71 mL of 5% sodium hydrogencarbonate aqueous solution,and once with 71 mL of water. To the resulting heptane layer was added71 mL of heptane, and the solution was washed by liquid-liquidextraction as follows: once with 71 mL of DMF and once with 71 mL ofacetonitrile. The heptane layer was concentrated under reduced pressureto afford 10.7 g of TIPS2-Dpm-C═O.

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.08 (m, 42H), 1.20-1.39 (m, 24H),1.41-1.49 (m, 4H), 1.49-1.57 (m, 4H), 1.71-1.85 (m, 4H), 3.67 (t, 4H),4.03 (t, 4H), 6.94 (d, 4H), 7.77 (d, 4H)

¹³C-NMR (100 MHz, CDCl₃) δ12.2 (6C), 18.2 (12C), 26.0 (2C), 26.2 (2C),29.2-29.8 (12C), 33.2 (2C), 63.7 (2C), 68.4 (2C), 114.0 (4C), 130.7(2C), 132.4 (4C), 162.6 (2C), 194.6

ESIMS MNa+ 889.8

(2) In a mixed solution of 7.1 mL of THF (anhydrous) and 0.36 mL ofmethanol, 0.81 g of TIPS2-Dpm-C═O (0.93 mmol) was dissolved, and 42 mgof sodium borohydride (1.12 mmol) was added to the solution, followed bystirring for 1.5 hours. To the reaction solution was added 0.89 mL of 1N hydrochloric acid to quench the reaction, 20.3 mL of CPME was added tothe solution, and the solution was washed once with 6.1 mL of 1 Nhydrochloric acid, once with 6.1 mL of 5% sodium hydrogencarbonateaqueous solution, and once with 6.1 mL of water. The organic layer wasconcentrated under reduced pressure. The resulting residue was dissolvedin 20.0 mL of heptane, and the solution was washed by liquid-liquidextraction with 10.0 mL of DMF. To the resulting heptane layer was added10.0 mL of heptane, and the solution was washed by liquid-liquidextraction with 10.0 mL of acetonitrile. The washing step byliquid-liquid extraction with heptane and acetonitrile was repeated oncemore, and the heptane layer was concentrated under reduced pressure toafford 0.81 g of TIPS2-Dpm-OH.

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 42H), 1.23-1.54 (m, 32H),1.57-1.71 (m, 4H), 1.79 (s, 1H), 3.68 (t, 8H), 5.61 (s, 1H), 6.84-6.89(m, 4H), 7.27-7.33 (m, 4H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.8 (6C), 18.7 (12C), 26.7 (2C), 26.8(2C), 30.2-30.5 (12C), 33.9 (2C), 64.1 (2C), 68.3 (2C), 75.9, 114.9(4C), 128.6 (4C), 137.8 (2C), 159.4 (2C)

(3) In 18.7 mL of THF, 0.81 g of TIPS2-Dpm-OH (0.93 mmol) was dissolved,and then 0.60 mL of diphenylphosphoryl azide (2.80 mmol) and 0.42 mL ofDBU (2.80 mmol) were added to the solution, followed by stirring at roomtemperature for 4 days. The reaction solution was diluted with 54.2 mLof CPME, and the solution was washed by liquid-liquid extraction asfollows: twice with 18.4 mL of 5% sodium hydrogencarbonate aqueoussolution and four times with 18.4 mL of 20% sodium chloride aqueoussolution. The organic layer was concentrated under reduced pressure. Theresidue was dissolved in 18.7 mL of heptane, and the solution was washedby liquid-liquid extraction with 9.3 mL of DMF. The washing step byliquid-liquid extraction with heptane and DMF was further repeated threetimes, and then the solution was washed once by liquid-liquid extractionwith 9.3 mL of water. To the resulting heptane layer was added 10.7 mLof heptane, and the solution was washed by liquid-liquid extraction with10.7 mL of acetonitrile. The washing step by liquid-liquid extractionwith heptane and acetonitrile was repeated once more, and then theheptane layer was concentrated under reduced pressure to give 0.59 g ofTIPS2-Dpm-N₃.

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.08 (m, 42H), 1.20-1.39 (m, 24H),1.41-1.49 (m, 4H), 1.49-1.57 (m, 4H), 1.71-1.81 (m, 4H), 3.67 (t, 4H),3.94 (t, 4H), 5.62 (s, 1H), 6.86 (d, 4H), 7.19 (d, 4H)

¹³C-NMR (100 MHz, CDCl₃) δ12.2 (6C), 18.2 (12C), 26.0 (2C), 26.2 (2C),29.2-29.8 (12C), 33.2 (2C), 63.7 (2C), 67.9,68.2 (2C), 114.7 (4C), 128.7(4C), 131.9 (2C), 159.0 (2C)

(4) In 2.8 mL of THF, 0.38 g of TIPS2-Dpm-N₃ (0.43 mmol) was dissolved,and 0.34 g of triphenylphosphine (1.23 mmol) and 0.31 mL of water (17.0mmol) were added to the solution, followed by stirring at 60° C. for 6hours. Then, the residue was dissolved in 4.2 mL of heptane, and thesolution was washed by liquid-liquid extraction with 4.2 mL of DMF. Thewashing step by liquid-liquid extraction with heptane and DMF wasfurther repeated twice. Then, 4.2 mL of heptane was added to the heptanelayer, and the solution was washed by liquid-liquid extraction with 4.2mL of acetonitrile/water mixture(50/50). The washing step byliquid-liquid extraction with heptane and acetonitrile/watermixture(50/50) was repeated once more. To the resulting heptane layerwas added 4.2 mL of heptane, and the solution was washed byliquid-liquid extraction with 4.2 mL of acetonitrile. The washing stepby liquid-liquid extraction with heptane and acetonitrile was repeatedonce more, then the heptane layer was concentrated under reducedpressure, and the resulting residue was purified by silica gelchromatography (heptane:ethyl acetate=17:1 to ethyl acetate) to afford0.30 g of TIPS2-Dpm-NH₂.

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.08 (m, 42H), 1.20-1.39 (m, 24H),1.41-1.49 (m, 4H), 1.49-1.57 (m, 4H), 1.71-1.81 (m, 4H), 1.98 (s, 2H),3.67 (t, 4H), 3.91 (t, 4H), 5.12 (s, 1H)6.80-6.84 (m, 4H), 7.22-7.26 (m,4H)

¹³C-NMR (100 MHz, CDCl₃) δ12.2 (6C), 18.2 (12C), 26.0 (2C), 26.2 (2C),29.5-29.8 (12C), 33.2 (2C), 58.6,63.7 (2C), 68.1 (2C), 114.5 (4C), 128.0(4C), 137.9 (2C), 158.2 (2C)

Example 2 Synthesis of TIPS2-Dpm-Cl

(Hereinafter, TIPS2-Dpm-Cl represents the structure in the abovescheme.)

(1) In a mixed solution of 1.8 mL of THF (anhydrous) and 90 μl ofmethanol, 0.24 g of TIPS2-Dpm-C═O (0.24 mmol) was dissolved, and 11 mgof sodium borohydride (0.28 mmol) was added to the solution, followed bystirring for 3 hours. To the reaction solution was added 0.2 mL of 1 Nhydrochloric acid to quench the reaction, 5.1 mL of CPME was added tothe solution, and the solution was washed twice with 1.5 mL of 1 Nhydrochloric acid and once with 1.5 mL of 20% sodium chloride aqueoussolution. To the organic layer was added 0.20 g of anhydrous magnesiumsulfate, and the mixture was stirred sufficiently, followed byfiltration. The filtrate was concentrated under reduced pressure to givea mixture containing TIPS2-Dpm-OH.

(2) The mixture obtained in the foregoing step was dissolved in 3.7 mLof chloroform, and then 3.6 μL of DMF (0.05 mmol) and 98 μL of pyridine(1.22 mmol) were added to the solution, followed by cooling to 5° C.Then, 81 μL of thionyl chloride (1.11 mmol) was added to the solution,and the solution was heated to room temperature and stirred for 1 hour.To the reaction solution was added 12.2 mL of heptane, and the solutionwas washed by liquid-liquid extraction with 12.2 mL of acetonitrile. Tothe resulting heptane layer were added 2.0 mL of heptane and 0.6 mL ofCPME, and the solution was washed by liquid-liquid extraction with 12.2mL of acetonitrile. To the resulting heptane layer was added 2.0 mL ofheptane, and the solution was washed by liquid-liquid extraction with12.2 mL of acetonitrile. The washing step by liquid-liquid extractionwith heptane and acetonitrile was repeated once more, and then theheptane layer was concentrated under reduced pressure to afford 81 mg ofTIPS2-Dpm-Cl.

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 42H), 1.23-1.38 (m, 28H),1.39-1.48 (m, 4H), 1.56-1.66 (m, 4H), 3.63 (t, 4H), 3.68 (t, 4H), 6.02(s, 1H), 6.76-6.82 (m, 4H), 7.27-7.32 (m, 4H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.8 (6C), 18.7 (12C), 26.7 (2C), 26.8(2C), 29.8-30.5 (12C), 33.9 (2C), 64.1 (2C), 65.1, 68.4 (2C), 115.0(4C), 129.9 (4C), 134.4 (2C), 159.8 (2C)

Example 3

Synthesis of TIPS2-Dpm-OH(C₈)

(Hereinafter, Br—(CH₂)₈-OTIPS, TIPS2-Dpm-C═O(C₈), and TIPS2-Dpm-OH(C₈)represent the respective structures in the above scheme.)

(1) In 12.2 mL of DMF, 1.51 g of Br—(CH₂)₈-OTIPS (4.13 mmol), 0.39 g of4,4′-dihydroxybenzophenone (1.83 mmol), and 0.91 g of potassiumcarbonate (6.60 mmol) were suspended, and the suspension was heated to85° C. and stirred for 2 hours. The reaction solution was filtered, andthe residue was washed with 25.7 mL of heptane. The filtrate wassubjected to liquid-liquid extraction. To the resulting heptane layerwas added 12.2 mL of heptane, and the solution was washed byliquid-liquid extraction with 12.2 mL of DMF. To the resulting heptanelayer was added 12.2 mL of heptane, and the solution was washed byliquid-liquid extraction as follows: once with 12.2 mL of 1 Nhydrochloric acid, once with 12.2 mL of 5% sodium hydrogencarbonateaqueous solution, and once with 12.2 mL of water. To the resultingheptane layer was added 12.2 mL of heptane, and the solution was washedby liquid-liquid extraction with 12.2 mL of acetonitrile twice. Theheptane layer was concentrated under reduced pressure, and the resultingresidue was purified by silica gel chromatography (heptane:ethylacetate=80:1 to ethyl acetate) to give 1.11 g of TIPS2-Dpm-C═O(C₈).

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.08 (m, 42H), 1.33-1.43 (m, 12H),1.43-1.64 (m, 8H), 1.82 (quin., 4H), 3.68 (t, 4H), 4.03 (t, 4H), 6.94(d, 4H), 7.77 (d, 4H)

ESIMS MH+ 783.5

(2) In a mixed solution of 6.4 mL of THF (anhydrous) and 0.32 mL ofmethanol, 0.66 g of TIPS2-Dpm-C═O(C₈) (0.85 mmol) was dissolved, and 38mg of sodium borohydride (1.01 mmol) was added to the solution, followedby stirring at room temperature for 3 hours. To the reaction solutionwas added 0.80 mL of 1 N hydrochloric acid to quench the reaction, 16.6mL of CPME was added to the solution, and the solution was washed twicewith 5.0 mL of 1 N hydrochloric acid, once with 5.0 mL of 5% sodiumhydrogencarbonate aqueous solution, and once with 5.0 mL of water. Tothe organic layer was added 0.66 g of anhydrous sodium sulfate, and themixture was stirred sufficiently, followed by filtration. The residuewas washed with 3.3 mL of heptane. The filtrate was concentrated underreduced pressure to afford 0.63 g of TIPS2-Dpm-OH(C₈).

¹H-NMR (400 MHz, Benzene-d₆) δ1.11-1.16 (m, 42H), 1.22-1.31 (m, 12H),1.31-1.43 (m, 4H), 1.52-1.66 (m, 9H), 3.66 (t, 8H), 5.59 (s, 1H),6.83-6.89 (m, 4H), 7.26-7.32 (m, 4H)

ESIMS MNa+ 807.6

Example 4

Synthesis of TIPS2-Dpm-OH(C₁₄)

(Hereinafter, Br—(CH₂)₁₄-OTIPS, TIPS2-Dpm-C═O(C₁₄), andTIPS2-Dpm-OH(C₁₄) represent the respective structures in the abovescheme.)

(1) TIPS2-Dpm-C═O(C₁₄) was obtained by a similar manner to thatdescribed for TIPS2-Dpm-C═O(C₈) above.

¹H-NMR (400 MHz, CDCl₃) δ1.03-1.07 (m, 42H), 1.20-1.40 (m, 36H),1.40-1.58 (m, 8H), 1.74-1.86 (m, 4H), 3.67 (t, 4H), 4.03 (t, 4H),6.91-6.96 (m, 4H), 7.73-7.79 (m, 4H)

ESIMS MH+ 951.8

(2) TIPS2-Dpm-OH(C₁₄) was obtained by a similar manner to that describedfor TIPS2-Dpm-OH(C₈) above.

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 42H), 1.23-1.40 (m, 36H),1.40-1.49 (m, 4H), 1.55-1.69 (m, 9H), 3.68 (t, 8H), 5.60 (s, 1H),6.85-6.90 (m, 4H), 7.28-7.33 (m, 4H)

ESIMS MNa+ 975.7

Example 5

Synthesis of TIPS2-Dpm-OH(C₈OC₂)

(Hereinafter, Br—(CH₂)₈—O—(CH₂)₂-OTIPS, TIPS2-Dpm-C═O(C₈OC₂), andTIPS2-Dpm-OH(C₈OC₂) represent the respective structures in the abovescheme.)

(1) In 4.5 mL of DMF, 0.62 g of Br—(CH₂)₈—O— (CH₂)₂-OTIPS (1.50 mmol),0.14 g of 4,4′-dihydroxybenzophenone (0.67 mmol), and 0.37 g ofpotassium carbonate (2.67 mmol) were suspended, and the suspension washeated to 85° C. and stirred for 2 hours 30 minutes. The reactionsolution was filtered, and the residue was washed with 9.3 mL ofheptane. The filtrate was subjected to liquid-liquid extraction. To theresulting heptane layer was added 4.5 mL of heptane, and the solutionwas washed by liquid-liquid extraction with 4.5 mL of DMF. To theresulting heptane layer was added 4.5 mL of heptane, and the solutionwas washed by liquid-liquid extraction as follows: once with 4.5 mL of 1N hydrochloric acid, once with 4.5 mL of 5% sodium hydrogencarbonateaqueous solution, and once with 4.5 mL of water. To the resultingheptane layer was added 4.5 mL of heptane, and the solution was washedby liquid-liquid extraction with 4.5 mL of acetonitrile. The washingstep by liquid-liquid extraction with heptane and acetonitrile wasrepeated once more. The heptane layer was concentrated under reducedpressure, and the resulting residue was purified by silica gelchromatography (heptane:ethyl acetate=40:1 to ethyl acetate) to give0.14 g of TIPS2-Dpm-C═O(C₈OC₂).

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.09 (m, 42H), 1.30-1.41 (m, 12H),1.41-1.52 (m, 4H), 1.52-1.63 (m, 4H), 1.74-1.86 (m, 4H), 3.48 (t, 4H),3.53 (t, 4H), 3.83 (t, 4H), 4.03 (t, 4H), 6.91-6.97 (m, 4H), 7.74-7.80(m, 4H)

ESIMS MH+ 871.6

(2) TIPS2-Dpm-OH(C₈OC₂) was obtained by a similar manner to thatdescribed for TIPS2-Dpm-OH(C₈) above.

¹H-NMR (400 MHz, Benzene-d₆) δ1.1-1.15 (m, 42H), 1.20-1.28 (m, 8H),1.28-1.40 (m, 8H), 1.53-1.69 (m, 9H), 3.38 (t, 4H), 3.49 (t, 4H), 3.67(t, 4H), 3.83 (t, 4H), 5.60 (s, 1H), 6.85-6.90 (m, 4H), 7.27-7.33 (m,4H)

ESIMS MNa+ 895.7

Example 6

Synthesis of TBDPS2-Dpm-OH

(Hereinafter Br—(CH₂)₁₁-OTBDPS, TBDPS2-Dpm-C═O, and TBDPS2-Dpm-OHrepresent the respective structures in the above scheme.)

(1) In 7.6 mL of DMF, 1.26 g of Br—(CH₂)₁₁-OTBDPS (2.56 mmol), 0.24 g of4,4′-dihydroxybenzophenone (1.14 mmol), and 0.57 g of potassiumcarbonate (4.10 mmol) were suspended, and the suspension was heated to85° C. and stirred for 3 hours. The reaction solution was filtered, andthe residue was washed with 15.9 mL of heptane. The filtrate wassubjected to liquid-liquid extraction. To the resulting heptane layerwas added 7.6 mL of heptane, and the solution was washed byliquid-liquid extraction with 7.6 mL of acetonitrile. To the resultingheptane layer was added 7.6 mL of heptane, and the solution was washedby liquid-liquid extraction as follows: once with 7.6 mL of 1 Nhydrochloric acid, once with 7.6 mL of 5% sodium hydrogencarbonateaqueous solution, and once with 7.6 mL of water. To the resultingheptane layer was added 7.6 mL of heptane, and the solution was washedby liquid-liquid extraction with 7.6 mL of acetonitrile twice. Theheptane layer was concentrated under reduced pressure, and the resultingresidue was purified by silica gel chromatography (heptane:ethylacetate=80:1 to ethyl acetate) to afford 0.76 g of TBDPS2-Dpm-C═O.

¹H-NMR (400 MHz, CDCl₃) δ1.05 (s, 1H), 1.23-1.42 (m, 24H), 1.42-1.61 (m,8H), 1.77-1.86 (m, 4H), 3.66 (t, 4H), 4.03 (t, 4H), 6.92-6.97 (m, 4H),7.35-7.45 (m, 12H), 7.65-7.70 (m, 8H), 7.75-7.80 (m, 4H)

ESIMS MNa+ 1053.5

(2) TBDPS2-Dpm-OH was obtained by a similar manner to that described forTIPS2-Dpm-OH(C₈) above.

¹H-NMR (400 MHz, Benzene-d₆) δ1.20 (s, 18H), 1.22-1.32 (m, 24H),1.32-1.43 (m, 4H), 1.56-1.68 (m, 9H), 3.68 (t, 4H), 3.71 (t, 4H), 5.59(s, 1H), 6.86-6.90 (m, 4H), 7.22-7.27 (m, 12H), 7.28-7.33 (m, 4H),7.79-7.84 (m, 8H)

ESIMS MNa+ 1055.6

Example 7

Synthesis of TIPS2-Dpm-OH(C₁₀—CONH—C₂)

(Hereinafter, Br— (CH₂)₁₀—CONH— (CH₂)₂—OTIPS,TIPS2-Dpm-C═O(C₁₀—CONH—C₂), and TIPS2-Dpm-OH(C₁₀—CONH—C₂) represent therespective structures in the above scheme.)

(1) In 7.4 mL of DMF, 1.44 g of Br—(CH₂)₁₀—CONH—(CH₂)₂-OTIPS (3.11mmol), 0.24 g of 4,4′-dihydroxybenzophenone (1.11 mmol), and 0.61 g ofpotassium carbonate (4.44 mmol) were suspended, and the suspension washeated to 115° C. and stirred for 2 hours 20 minutes. The reactionsolution was filtered, and the residue was washed with 73.9 mL ofheptane. The filtrate was concentrated under reduced pressure. To theresulting residue was added 22 mL of water, and the resultingprecipitate was filtered. The precipitate was further washed with water,and the precipitate was filtered again. The resulting precipitate waswashed with 22 mL of acetonitrile, and the precipitate was filtered. Theprecipitate was further washed with acetonitrile, and the precipitatewas filtered again. The resulting precipitate was dried under reducedpressure to give 0.80 g of TIPS2-Dpm-C═O(C₁₀—CONH—C₂).

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.08 (m, 42H), 1.26-1.40 (m, 20H), 1.46(quin., 4H), 1.62 (quin., 4H), 1.81 (quin., 4H), 2.18 (t, 4H), 3.40 (q,4H), 3.76 (t, 4H), 4.02 (t, 4H), 5.88 (t, 2H), 6.91-6.96 (m, 4H),7.74-7.79 (m, 4H)

ESIMS MH+ 981.7

(2) In a mixed solution of 2.0 mL of THF (anhydrous) and 0.10 mL ofmethanol, 0.26 g of TIPS2-Dpm-C═O(C₁₀—CONH—C₂) (0.26 mmol) wasdissolved, and 12 mg of sodium borohydride (0.32 mmol) was added to thesolution, followed by stirring at room temperature for 3 hours 20minutes. To the reaction solution was added 0.25 mL of 1 N hydrochloricacid to quench the reaction, 6.5 mL of CPME was added to the solution,and the solution was washed twice with 1.9 mL of 1 N hydrochloric acid,once with 1.9 mL of 5% sodium hydrogencarbonate aqueous solution, andonce with 1.9 mL of water. To the organic layer was added 0.26 g ofanhydrous sodium sulfate, and the mixture was stirred sufficiently,followed by filtration. The filtrate was concentrated under reducedpressure to afford 0.21 g of TIPS2-Dpm-OH(C₁₀—CONH—C₂).

ESIMS MNa+ 1005.7

Example 8

Synthesis of TIPS4-Dpm-OH(C₁₀—CONH—CH(CH₂)₂)

(Hereinafter, Br— (CH₂)₁₀—CONH—CH(CH₂—OTIPS)₂,TIPS4-Dpm-C═O(C₁₀—CONH—CH(CH₂)₂), and TIPS4-Dpm-OH(C₁₀—CONH—CH(CH₂)₂)represent the respective structures in the above scheme.)

(1) In 8.7 mL of DMF, 2.04 g of Br—(CH₂)₁₀—CONH—CH(CH₂—OTIPS)₂ (3.14mmol), 0.28 g of 4,4′-dihydroxybenzophenone (1.31 mmol), and 0.69 g ofpotassium carbonate (4.97 mmol) were suspended, and the suspension washeated to 115° C. and stirred for 8 hours 30 minutes. In addition, 0.34g of Br—(CH₂)₁₀—CONH—CH(CH₂-OTIPS)₂ (0.52 mmol) was added to thesuspension, and the suspension was stirred at 115° C. for 1 hour. Thereaction solution was filtered, and the filtrate was washed with 18.3 mLof heptane. The filtrate was subjected to liquid-liquid extraction. Tothe resulting heptane layer was added 8.7 mL of heptane, and thesolution was washed by liquid-liquid extraction with 8.7 mL of DMF. Tothe resulting heptane layer was added 8.7 mL of heptane, and thesolution was washed by liquid-liquid extraction as follows: once with8.7 mL of 1 N hydrochloric acid, once with 8.7 mL of 5% sodiumhydrogencarbonate aqueous solution, and once with 8.7 mL of water. Tothe resulting heptane layer was added 8.7 mL of heptane, and thesolution was washed by liquid-liquid extraction with 8.7 mL ofacetonitrile. The washing step by liquid-liquid extraction with heptaneand acetonitrile was repeated once more. The heptane layer wasconcentrated under reduced pressure to give 0.64 g ofTIPS4-Dpm-C═O(C₁₀—CONH—CH(CH₂)₂).

¹H-NMR (400 MHz, CDCl₃) δ1.03-1.08 (m, 84H), 1.22-1.40 (m, 20H),1.40-1.51 (m, 4H), 1.51-1.69 (m, 4H), 1.70-1.85 (m, 4H), 2.16 (t, 4H),3.62-3.70 (m, 4H), 3.84-3.91 (m, 4H), 3.94-4.05 (m, 6H), 5.84 (d, 2H),6.90-6.96 (m, 4H), 7.74-7.79 (m, 4H)

ESIMS MH+ 1353.9

(2) In a mixed solution of 2.9 mL of THF (anhydrous) and 0.15 mL ofmethanol, 0.52 g of TIPS4-Dpm-C═O(C₁₀—CONH—CH(CH₂)₂) (0.38 mmol) wasdissolved, and 17 mg of sodium borohydride (0.46 mmol) was added to thesolution, followed by stirring at room temperature for 3 hours 45minutes. To the reaction solution was added 0.36 mL of 1 N hydrochloricacid to quench the reaction, 12.9 mL of ethyl acetate was added to thesolution, and the solution was washed twice with 3.9 mL of 1 Nhydrochloric acid, once with 3.9 mL of 5% sodium hydrogencarbonateaqueous solution, and once with 3.9 mL of water. To the organic layerwas added 0.52 g of anhydrous sodium sulfate, and the mixture wasstirred sufficiently, followed by filtration. The filtrate wasconcentrated under reduced pressure to afford 0.45 g ofTIPS4-Dpm-OH(C₁₀—CONH—CH(CH₂)₂).

ESIMS MNa+ 1378.9

Example 9

Synthesis of TIPS4-Dpm-NH(CH₂)₂CH₃ (C₁₀—CONH—CH(CH₂)₂)

(Hereinafter, TIPS4-Dpm-Cl(C₁₀—CONH—CH(CH₂)₂) andTIPS4-Dpm-NH(CH₂)₂CH₃(C₁₀—CONH—CH(CH₂)₂) represent the respectivestructures in the above scheme.)

(1) In 5.3 mL of chloroform, 0.45 g of TIPS4-Dpm-OH(C₁₀—CONH—CH(CH₂)₂)(0.33 mmol) was dissolved, and then 5 μL of DMF (0.07 mmol) and 59 μL ofpyridine (0.73 mmol) were added to the solution, followed by cooling to5° C. Then, 48 μL of thionyl chloride (0.66 mmol) was added to thesolution, and the solution was heated to room temperature and stirredfor 1 hour 15 minutes. To the reaction solution were added 27.6 mL ofheptane and 1.3 mL of CPME, and the solution was washed by liquid-liquidextraction with 26.7 mL of acetonitrile. To the resulting heptane layerwere added 4.5 mL of heptane and 1.3 mL of CPME, and the solution waswashed by liquid-liquid extraction with 26.7 mL of acetonitrile. To theresulting heptane layer was added 4.5 mL of heptane, and the solutionwas washed by liquid-liquid extraction with 26.7 mL of acetonitrile. Theheptane layer was concentrated under reduced pressure to give a mixturecontaining TIPS4-Dpm-Cl(C₁₀—CONH—CH(CHA)₂).

(2) The mixture obtained in the foregoing step was dissolved in 2.5 mLof chloroform, and then 56 μL of propyl amine (0.67 mmol) and 0.12 mL ofDIPEA (0.68 mmol) were added to the solution, followed by stirring atroom temperature for 30 minutes. To the reaction solution was added 10.0mL of CPME, and the solution was washed by liquid-liquid extraction asfollows: twice with 6.0 mL of 0.5 N hydrochloric acid, once with 6.0 mLof 5% sodium hydrogencarbonate aqueous solution, and once with 6.0 mL of20% sodium chloride aqueous solution. To the organic layer was added0.90 g of anhydrous sodium sulfate, and the mixture was stirredsufficiently, followed by filtration. The filtrate was concentratedunder reduced pressure to afford 0.25 g of TIPS4-Dpm-NH(CH₂)₂CH₃(C₁₀—CONH—CH(CH₂)₂).

ESIMS MH+ 1396.9

Example 10

Synthesis of TIPS2-Dpm-NOH(C₁₄)

(Hereinafter, TIPS2-Dpm-NOH(C₁₄) represents the structure in the abovescheme.)

(1) In 0.90 mL of CPME, 0.19 g of TIPS2-Dpm-C═O(C₁₄) (0.20 mmol) wasdissolved, and then 41 mg of hydroxylamine hydrochloride (0.59 mmol) wasadded to the solution, followed by cooling to 5° C. To the solution wasadded 184 μL of pyridine (1.78 mmol), and the solution was heated to 90°C. and stirred for 22 hours 15 minutes. In addition, 41 mg ofhydroxylamine hydrochloride (0.59 mmol) and 306 μL of pyridine (2.96mmol) were added to the solution, and the solution was stirred at 90° C.for 7 hours 30 minutes. In addition, 124 mg of hydroxylaminehydrochloride (1.78 mmol) and 184 μL of pyridine (1.78 mmol) were addedto the solution, and the solution was stirred at 90° C. for 2 hours. Inaddition, 247 mg of hydroxylamine hydrochloride (3.55 mmol) and 184 μLof pyridine (1.78 mmol) were added to the solution, and the solution wasstirred at 90° C. for 15 hours. In addition, 247 mg of hydroxylaminehydrochloride (3.55 mmol) and 184 μL of pyridine (1.78 mmol) were addedto the solution, and the solution was stirred at 90° C. for 6 hours 30minutes. In addition, 247 mg of hydroxylamine hydrochloride (3.55 mmol),367 μL of pyridine (3.56 mmol), and 1.0 mL of CPME were added to thesolution, and the solution was stirred at 90° C. for 17 hours 15minutes. The reaction solution was cooled to 5° C., and the reaction wasquenched with 15 mL of 1 N hydrochloric acid. To the solution was added25 mL of heptane, and the solution was washed by liquid-liquidextraction as follows: three times with 15 mL of 1 N hydrochloric acid,three times with 15 mL of 5% sodium hydrogencarbonate aqueous solution,and once with 15 mL of water. To the resulting heptane layer was added15 mL of heptane, and the solution was washed by liquid-liquidextraction with 15 mL of acetonitrile. The washing step by liquid-liquidextraction with heptane and acetonitrile was repeated once more, andthen the heptane layer was concentrated under reduced pressure to afford0.14 g of TIPS2-Dpm-NOH(C₁₄).

ESIMS MH+ 966.9

Example 11

Synthesis of TIPS2-Dpm(OMe)₂-NH₂

(Hereinafter, TIPS2-Dpm(OMe)₂-C═O, TIPS2-Dpm(OMe)₂-OH,TIPS2-Dpm(OMe)₂-N₃, and TIPS2-Dpm(OMe)₂-NH₂ represent the respectivestructures in the above scheme.)

(1) In 41 mL of DMF, 5.59 g of Br—(CH₂)₁₁-OTIPS (13.7 mmol), 1.67 g of2,2′-dihydroxy-4,4′-dimethoxybenzophenone (6.09 mmol), and 3.03 g ofpotassium carbonate (22.9 mmol) were suspended, and the suspension washeated to 85° C. and stirred for 21 hours. The reaction solution wasfiltered, and the residue was washed with 85 mL of heptane. The filtratewas subjected to liquid-liquid extraction. To the resulting heptanelayer was added 41 mL of heptane, and the solution was washed byliquid-liquid extraction with 41 mL of DMF. The washing step byliquid-liquid extraction with heptane and DMF was repeated once more. Tothe resulting heptane layer was added 41 mL of heptane, and the solutionwas washed by liquid-liquid extraction as follows: once with 41 mL of 1N hydrochloric acid, once with 41 mL of 5% sodium hydrogencarbonateaqueous solution, and twice with 41 mL of water. To the resultingheptane layer was added 41 mL of heptane, and the solution was washed byliquid-liquid extraction as follows: once with 41 mL of DMF and twicewith 41 mL of acetonitrile. The heptane layer was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (heptane:ethyl acetate=45:1 to 20:1) to give 2.03g of TIPS2-Dpm(OMe)₂-C═O (yield: 35.9%).

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 42H), 1.23-1.38 (m, 28H),1.41-1.51 (m, 4H), 1.57-1.67 (m, 4H), 3.38 (s, 6H), 3.51 (t, 4H), 3.70(t, 4H), 6.33 (dd, 2H), 6.41 (d, 2H), 7.93 (d, 2H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.8 (6C), 18.7 (12C), 26.7 (2C), 26.8(2C), 29.9-30.6 (12C), 33.9 (2C), 55.3 (2C), 64.1 (2C), 68.6 (2C), 99.8(2C), 104.7 (2C), 126.6 (2C), 132.8 (2C), 160.4 (2C), 163.9 (2C), 192.7

(2) In a mixed solution of 16.3 mL of THF (anhydrous) and 0.81 mL ofmethanol, 1.98 g of TIPS2-Dpm(OMe)₂-C═O (2.14 mmol) was dissolved, and97 mg of sodium borohydride (2.56 mmol) was added to the solution,followed by stirring for 2 hours. To the reaction solution was added 2.0mL of 1 N hydrochloric acid to quench the reaction, 50 mL of CPME wasadded to the solution, and the solution was washed once with 15 mL of 1N hydrochloric acid, twice with 15 mL of water, once with 15 mL of 5%sodium hydrogencarbonate aqueous solution, and twice with 15 mL ofwater. The organic layer was concentrated under reduced pressure. Theresulting residue was dissolved in 50 mL of heptane, and the solutionwas washed by liquid-liquid extraction with 25 mL of DMF. To theresulting heptane layer was added 25 mL of heptane, and the solution waswashed by liquid-liquid extraction with 25 mL of acetonitrile. Thewashing step by liquid-liquid extraction with heptane and acetonitrilewas repeated once more, and the heptane layer was concentrated underreduced pressure to give a mixture containing TIPS2-Dpm(OMe)₂-OH.

(3) The mixture obtained in the foregoing step was dissolved in 42.7 mLof THF, and then 2.34 g of bis(p-nitrophenyl)phosphoryl azide (6.41mmol) and 0.96 mL of DBU (6.41 mmol) were added to the solution,followed by stirring at room temperature for 1 hour. The reactionsolution was diluted with 124 mL of CPME, and the solution was washed byliquid-liquid extraction with 42 mL of 5% sodium hydrogencarbonateaqueous solution six times. The solution was concentrated under reducedpressure. The residue was dissolved in 128 mL of heptane, and thesolution was washed by liquid-liquid extraction with 43 mL of DMF. Thewashing step by liquid-liquid extraction with heptane and DMF wasfurther repeated twice, and then the solution was washed byliquid-liquid extraction with 43 mL of acetonitrile twice. The resultingheptane layer was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (heptane:ethylacetate=35:1) to give 0.74 g of TIPS2-Dpm(OMe)₂-N₃ ((yield: 36.2%, 2steps).

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 42H), 1.23-1.38 (m, 28H),1.41-1.51 (m, 4H), 1.57-1.67 (m, 4H), 3.37 (s, 6H), 3.61-3.73 (m, 8H),6.35 (dd, 2H), 6.53 (d, 2H), 6.78 (s, 1H), 7.40 (d, 2H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.8 (6C), 18.7 (12C), 26.7 (2C), 26.8(2C), 29.8-30.6 (12C), 33.9 (2C), 55.2 (2C), 58.0, 64.1 (2C), 68.4 (2C),100.1 (2C), 104.3 (2C), 121.8 (2C), 129.8 (2C), 158.2 (2C), 161.4 (2C)

(4) In 4.9 mL of THF, 0.70 g of TIPS2-Dpm(OMe)₂-N₃ (0.73 mmol) wasdissolved, and 0.57 g of triphenylphosphine (2.18 mmol) and 0.53 mL ofwater (29.1 mmol) were added to the solution, followed by stirring at60° C. for 6 hours. The reaction solution was concentrated under reducedpressure. Then, the residue was dissolved in 14.6 mL of heptane, and thesolution was washed by liquid-liquid extraction with 7.3 mL of DMF. Thewashing step by liquid-liquid extraction with heptane and DMF wasfurther repeated twice. Then, 7.3 mL of heptane was added to the heptanelayer, and the solution was washed by liquid-liquid extraction with 7.3mL of acetonitrile/water mixture (50/50). The washing step byliquid-liquid extraction with heptane and acetonitrile/water mixture(50/50) was repeated once more. To the resulting heptane layer was added7.3 mL of heptane, and the solution was washed by liquid-liquidextraction with 7.3 mL of acetonitrile. The washing step byliquid-liquid extraction with heptane and acetonitrile was repeated oncemore, then the heptane layer was concentrated under reduced pressure,and the resulting residue was purified by silica gel chromatography(heptane:ethyl acetate=13:1 to ethyl acetate) to afford 0.34 g ofTIPS2-Dpm(OMe)₂-NH₂ (yield: 50.3%).

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 42H), 1.23-1.38 (m, 28H),1.41-1.51 (m, 4H), 1.57-1.67 (m, 4H), 1.71 (s, 2H), 3.44 (s, 6H),3.63-3.73 (m, 8H), 6.02 (s, 1H), 6.44 (dd, 2H), 6.58 (d, 2H), 7.49 (d,2H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.8 (6C), 18.7 (12C), 26.8 (4C),29.8-30.6 (12C), 33.9 (2C), 48.9, 55.3 (2C), 64.1 (2C), 68.2 (2C), 100.2(2C), 104.1 (2C), 128.3 (2C), 129.1 (2C), 158.2 (2C), 160.5 (2C)

Example 12

Synthesis of TIPS3-Dpm-NH₂

(Hereinafter, TIPS3-Dpm-C═O, TIPS3-Dpm-OH, TIPS3-Dpm-N₃, andTIPS3-Dpm-NH₂ represent the respective structures in the above scheme.)

(1) In 30 mL of DMF, 6.35 g of Br—(CH₂)₁₁-OTIPS (15.59 mmol), 1.04 g of2,4,4′-trihydroxybenzophenone (4.52 mmol), and 3.12 g of potassiumcarbonate (22.59 mmol) were suspended, and the suspension was heated to85° C. and stirred for 15.5 hours. The reaction solution was filtered,and the residue was washed with 63 mL of heptane. The filtrate wassubjected to liquid-liquid extraction. To the resulting heptane layerwas added 30 mL of heptane, and the solution was washed by liquid-liquidextraction with 30 mL of DMF. The washing step by liquid-liquidextraction with heptane and DMF was repeated once more. To the resultingheptane layer was added 30 mL of heptane, and the solution was washed byliquid-liquid extraction as follows: once with 30 mL of 1 N hydrochloricacid, once with 30 mL of 5% sodium hydrogencarbonate aqueous solution,and twice with 30 mL of water. To the resulting heptane layer was added30 mL of heptane, and the solution was washed by liquid-liquidextraction as follows: once with 30 mL of DMF and twice with 30 mL ofacetonitrile. The resulting heptane layer was concentrated under reducedpressure to give 5.96 g of TIPS3-Dpm-C═O.

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.08 (m, 63H), 1.20-1.57 (m, 50H),1.74-1.84 (m, 4H), 3.64-3.69 (m, 6H), 3.83 (t, 2H), 3.99 (t, 4H), 6.45(d, 1H), 6.52 (dd, 1H), 6.83-6.87 (m, 2H), 7.36 (d, 1H), 7.70-7.76 (m,2H)

¹³C-NMR (100 MHz, CDCl₃) δ 12.2 (9C), 18.2 (18C), 25.9, 26.10 (3C), 26.2(2C), 29.1-29.8 (18C), 33.2 (3C), 63.7 (3C), 68.3, 68.4, 68.5, 99.9,105.3, 113.8 (2C), 122.4, 131.7, 132.0 (3C), 158.8, 162.7, 162.8, 195.0

(2) In a mixed solution of 5.8 mL of THF (anhydrous) and 0.29 mL ofmethanol, 0.92 g of TIPS3-Dpm-C═O (0.76 mmol) was dissolved, and 34 mgof sodium borohydride (0.91 mmol) was added to the solution, followed bystirring for 3 hours. To the reaction solution was added 0.72 mL of 1 Nhydrochloric acid to quench the reaction, 23.0 mL of CPME was added tothe solution, and the solution was washed once with 6.9 mL of 1 Nhydrochloric acid, once with 6.9 mL of 5% sodium hydrogencarbonateaqueous solution, and once with 6.9 mL of water. The organic layer wasconcentrated under reduced pressure. The resulting residue was dissolvedin 23.0 mL of heptane, and the solution was washed by liquid-liquidextraction with 11.0 mL of DMF. To the resulting heptane layer was added11.0 mL of heptane, and the solution was washed by liquid-liquidextraction with 11.0 mL of acetonitrile. The washing step byliquid-liquid extraction with heptane and acetonitrile was repeated oncemore, and then the heptane layer was concentrated under reduced pressureto give a mixture containing TIPS3-Dpm-OH.

(3) The mixture obtained in the foregoing step was dissolved in 15.2 mLof THF, and then 0.83 g of bis(p-nitrophenyl)phosphoryl azide (2.28mmol) and 0.34 mL of DBU (2.28 mmol) were added to the solution,followed by stirring at room temperature for 1 hour. The reactionsolution was diluted with 44.1 mL of CPME, and the solution was washedby liquid-liquid extraction with 15.0 mL of 5% sodium hydrogencarbonateaqueous solution twice. The resulting organic layer was concentratedunder reduced pressure. The residue was dissolved in 30.0 mL of heptane,and the solution was washed by liquid-liquid extraction as follows: oncewith 15.0 mL of acetonitrile and twice with 7.6 mL of water. To theresulting heptane layer was added 15.2 mL of heptane, and the solutionwas washed by liquid-liquid extraction with 7.6 mL of DMF. The washingstep by liquid-liquid extraction with heptane and DMF was furtherrepeated three times, then the solution was washed by liquid-liquidextraction with 7.6 mL of acetonitrile three times, and the heptanelayer was concentrated under reduced pressure to give 0.63 g ofTIPS3-Dpm-N₃.

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 63H), 1.20-1.51 (m, 50H),1.59-1.66 (m, 4H), 3.64-3.75 (m, 12H), 6.25 (s, 1H), 6.45 (dd, 1H), 6.57(d, 1H), 6.84-6.88 (m, 2H), 7.33-7.37 (m, 2H) 7.39 (d, 1H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.8 (9C), 18.7 (18C), 26.7 (3C), 26.8(2C), 26.9, 29.8-30.5 (18C), 33.9 (3C), 63.2, 64.1 (3C), 68.3, 68.4,68.5, 100.7, 105.3, 115.0 (2C), 121.8, 129.5 (2C), 129.8, 132.8, 158.1,159.6, 161.2

(4) In 2.9 mL of THF, 0.53 g of TIPS3-Dpm-N₃ (0.43 mmol) was dissolved,and 0.34 g of triphenylphosphine (1.28 mmol) and 0.31 mL of water (17.1mmol) were added, followed by stirring at 60° C. for 6 hours. Thereaction solution was concentrated under reduced pressure. The residuewas dissolved in 8.6 mL of heptane, and the solution was washed byliquid-liquid extraction with 4.3 mL of DMF. The washing step byliquid-liquid extraction with heptane and DMF was further repeatedtwice. Then, 4.3 mL of heptane was added to the heptane layer, and thesolution was washed by liquid-liquid extraction with 4.3 mL ofacetonitrile/water mixture (50/50). The washing step by liquid-liquidextraction with heptane and acetonitrile/water mixture (50/50) wasrepeated once more. To the resulting heptane layer was added 4.3 mL ofheptane, and the solution was washed by liquid-liquid extraction with4.3 mL of acetonitrile. The washing step by liquid-liquid extractionwith heptane and acetonitrile was repeated once more, then the heptanelayer was concentrated under reduced pressure, and the resulting residuewas purified by silica gel chromatography (heptane:ethyl acetate=17:1 toethyl acetate) to afford 0.25 g of TIPS3-Dpm-NH₂.

¹H-NMR (400 MHz, Benzene-d₆) δ1.12-1.16 (m, 63H), 1.20-1.51 (m, 50H),1.58-1.68 (m, 6H), 3.56-3.75 (m, 10H), 3.80 (t, 2H), 5.60 (s, 1H), 6.53(dd, 1H), 6.60 (d, 1H), 6.92-6.98 (m, 2H), 7.53 (d, 1H), 7.54-7.59 (m,2H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.8 (9C), 18.7 (18C), 26.7 (2C), 26.8(2C), 26.9 (2C), 29.6-30.5 (18C), 33.9 (3C), 54.0, 64.1 (3C), 68.2,68.3, 68.4, 100.8, 105.1, 114.8 (2C), 128.3, 128.9, 129.1 (2C), 138.9,158.0, 158.9, 160.2

Example 13

Synthesis of TIPS6-Dpm-NH₂

(Hereinafter, Br—(CH₂)₁₀—CONH—C(CH₂OTIPS)₃, TIPS6-Dpm-C═O, TIPS6-Dpm-OH,TIPS6-Dpm-N₃, and TIPS6-Dpm-NH₂ represent the respective structures inthe above scheme.)

(1) In 42 mL of DMF, 13.11 g of Br—(CH₂)₁₀—CONH—C(CH₂OTIPS)₃ (15.66mmol), 1.36 g of 4,4′-dihydroxybenzophenone (6.34 mmol), and 2.93 g ofpotassium carbonate (21.17 mmol) were suspended, the suspension washeated to 110° C. and stirred for 3 hours, and then heated to 120° C.and stirred for 1 hour. The reaction solution was filtered, and theresidue was washed with 89 mL of heptane. The filtrate was subjected toliquid-liquid extraction. To the resulting heptane layer was added 42 mLof heptane, and the solution was washed by liquid-liquid extraction with42 mL of DMF. The washing step by liquid-liquid extraction with heptaneand DMF was repeated once more. To the resulting heptane layer was added42 mL of heptane, and the solution was washed by liquid-liquidextraction as follows: once with 42 mL of 1 N hydrochloric acid, oncewith 42 mL of 5% sodium hydrogencarbonate aqueous solution, and twicewith 42 mL of water. To the resulting heptane layer was added 85 mL ofheptane, and the solution was washed by liquid-liquid extraction asfollows: once with 42 mL of DMF and twice with 42 mL of acetonitrile.The heptane layer was concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (heptane:ethylacetate=25:1 to 15:1) to give 5.36 g of TIPS6-Dpm-C═O (yield: 49.0%).

¹H-NMR (400 MHz, Benzene-d₆) δ1.15-1.20 (m, 126H), 1.23-1.38 (m, 24H),1.56-1.65 (m, 4H), 1.71-1.82 (m, 4H), 2.20 (t, 4H), 3.61 (t, 4H), 4.43(s, 12H), 5.90 (s, 2H), 6.77-6.81 (m, 4H), 7.89-7.95 (m, 4H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.7 (18C), 18.7 (36C), 26.6 (2C), 26.7(2C), 29.8-30.3 (12C), 38.2 (2C), 62.3 (6C), 62.8 (2C), 68.5 (2C), 114.6(4C), 131.9 (2C), 132.9 (4C), 163.0 (2C), 172.3 (2C), 193.8

(2) In a mixed solution of 22.9 mL of THF (anhydrous) and 1.15 mL ofmethanol, 5.19 g of TIPS6-Dpm-C═O (3.01 mmol) was dissolved, and 0.14 gof sodium borohydride (3.61 mmol) was added to the solution, followed bystirring for 2 hours. To the reaction solution was added 2.9 mL of 1 Nhydrochloric acid to quench the reaction, 130 mL of CPME was added tothe solution, and the solution was washed once with 39 mL of 1 Nhydrochloric acid and three times with 39 mL of water. The organic layerwas concentrated under reduced pressure. The resulting residue wasdissolved in 130 mL of heptane, and the solution was washed byliquid-liquid extraction with 65 mL of DMF. To the resulting heptanelayer was added 65 mL of heptane, and the solution was washed byliquid-liquid extraction with 65 mL of acetonitrile. The washing step byliquid-liquid extraction with heptane and acetonitrile was repeated oncemore, and then the heptane layer was concentrated under reduced pressureto give a mixture containing TIPS6-Dpm-OH.

(3) The mixture obtained in the foregoing step was dissolved in 60 mL ofTHF, and 3.29 g of bis(p-nitrophenyl)phosphoryl azide (9.02 mmol) and1.35 mL of DBU (9.02 mmol) were added to the solution, followed bystirring at room temperature for 1 hour. The reaction solution wasdiluted with 174 mL of CPME, and the solution was washed byliquid-liquid extraction as follows: once with 59 mL of 5% sodiumhydrogencarbonate aqueous solution and six times with 500 mL of water.The solution was concentrated under reduced pressure. The residue wasdissolved in 120 mL of heptane, and the solution was washed byliquid-liquid extraction with 60 mL of DMF. The washing step byliquid-liquid extraction with heptane and DMF was repeated once more. Tothe resulting heptane layer was added 60 mL of heptane, and the solutionwas washed by liquid-liquid extraction with 60 mL of acetonitrile. Thewashing step by liquid-liquid extraction with heptane and acetonitrilewas repeated once more, and then the heptane layer was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (heptane:ethyl acetate=40:1 to 20:1) to give 1.36g of TIPS6-Dpm-N₃ (yield: 31.0%, 2 steps).

¹H-NMR (400 MHz, Benzene-d₆) δ1.15-1.20 (m, 126H), 1.23-1.38 (m, 24H),1.58-1.67 (m, 4H), 1.70-1.79 (m, 4H), 2.19 (t, 4H), 3.64 (t, 4H), 4.42(s, 12H), 5.36 (s, 1H), 5.89 (s, 2H), 6.80-6.85 (m, 4H), 7.13-7.18 (m,4H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.7 (18C), 13.7 (36C), 26.6 (2C), 26.8(2C), 29.8-30.3 (12C), 38.2 (2C), 62.3 (6C), 62.8 (2C), 68.3 (2C), 68.4,115.2 (4C), 129.4 (4C), 132.8 (2C), 159.8 (2C), 172.3 (2C)

(4) In 4.72 mL of THF, 1.24 g of TIPS6-Dpm-N₃ (0.71 mmol) was dissolved,and 0.56 g of triphenylphosphine (2.13 mmol) and 0.51 mL of water (28.33mmol) were added to the solution, followed by stirring at 60° C. for 6hours. The reaction solution was concentrated under reduced pressure.The residue was dissolved in 14.2 mL of heptane, and the solution waswashed by liquid-liquid extraction with 7.1 mL of DMF. The washing stepby liquid-liquid extraction with heptane and DMF was further repeatedtwice. Then, 7.1 mL of heptane was added to the heptane layer, and thesolution was washed by liquid-liquid extraction with 7.1 mL ofacetonitrile/water mixture (50/50). The washing step by liquid-liquidextraction with heptane and acetonitrile/water mixture (50/50) wasrepeated once more. To the resulting heptane layer was added 7.1 mL ofheptane, and the solution was washed by liquid-liquid extraction with7.1 mL of acetonitrile. The washing step by liquid-liquid extractionwith heptane and acetonitrile was repeated once more, then the heptanelayer was concentrated under reduced pressure, and the resulting residuewas purified by silica gel chromatography (heptane:ethyl acetate=15:1 toethyl acetate) to afford 1.13 g of TIPS6-Dpm-NH₂ (yield: 92.2%).

¹H-NMR (400 MHz, Benzene-d₆) δ1.15-1.20 (m, 126H), 1.23-1.38 (m, 24H),1.60-1.82 (m, 10H), 2.19 (t, 4H), 3.70 (t, 4H), 4.43 (s, 12H), 4.97 (s,1H), 5.90 (s, 2H), 6.87-6.92 (m, 4H), 7.32-7.37 (m, 4H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.7 (18C), 18.6 (36C), 26.6 (2C), 26.8(2C), 29.8-30.3 (12C), 38.3 (2C), 59.4, 62.3 (6C), 62.8 (2C), 68.3 (2C),115.0 (4C), 128.7 (4C), 139.4 (2C), 159.0 (2C), 172.3 (2C)

Example 14

Synthesis of TIPS9-Dpm-NH₂

(Hereinafter, TIPS9-Dpm-C═O, TIPS9-Dpm-OH, TIPS9-Dpm-N₃, andTIPS9-Dpm-NH₂ represent the respective structures in the above scheme.)

(1) In 7.2 mL of DMF, 3.36 g of Br—(CH₂)₁₀—CONH—C(CH₂OTIPS)₃ (4.02mmol), 0.25 g of 2,4,4′-trihydroxybenzophenone (1.09 mmol), and 0.75 gof potassium carbonate (5.43 mmol) was suspended, and the suspension washeated to 120° C. and stirred for 5 hours. The reaction solution wasfiltered, and the residue was washed with 15.2 mL of heptane. Thefiltrate was subjected to liquid-liquid extraction. To the resultingheptane layer was added 7.2 mL of heptane, and the solution was washedby liquid-liquid extraction with 7.2 mL of DMF. The washing step byliquid-liquid extraction with heptane and DMF was repeated once more. Tothe resulting heptane layer was added 7.2 mL of heptane, and thesolution was washed by liquid-liquid extraction as follows: once with7.2 mL of 1 N hydrochloric acid, once with 7.2 mL of 5% sodiumhydrogencarbonate aqueous solution, and twice with 7.2 mL of water. Tothe resulting heptane layer was added 14.5 mL of heptane, and thesolution was washed by liquid-liquid extraction as follows: once with7.2 mL of DMF and twice with 7.2 mL of acetonitrile. The resultingheptane layer was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (heptane:ethylacetate=20:1 to 10:1) to give 1.81 g of TIPS9-Dpm-C═O (yield: 66.7%).

¹H-NMR (400 MHz, Benzene-d₆) δ1.15-1.20 (m, 189H), 1.23-1.38 (m, 36H),1.50-1.82 (m, 12H), 2.16-2.26 (m, 6H), 3.58 (t, 2H), 3.63 (t, 2H), 3.73(t, 2H), 4.43 (s, 18H), 5.91 (s, 3H), 6.42 (dd, 1H), 6.59 (d, 1H),6.78-6.83 (m, 2H), 7.60 (d, 1H), 8.03-8.08 (m, 2H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.7 (27C), 18.7 (54C), 26.5, 26.6 (3C),26.7, 26.8, 29.7-30.4 (18C), 38.2 (3C), 62.3 (9C), 62.8 (3C), 68.5 (2C),68.8, 101.0, 105.7, 114.4 (2C), 124.0, 132.3, 132.6 (2C), 133.2, 159.4,163.1, 163.3, 172.3 (3C), 194.1

(2) In a mixed solution of 5.1 mL of THF (anhydrous) and 0.26 mL ofmethanol, 1.69 g of TIPS9-Dpm-C═O (0.68 mmol) was dissolved, and 31 mgof sodium borohydride (0.81 mmol) was added to the solution, followed bystirring for 2.5 hours. To the reaction solution was added 0.64 mL of 1N hydrochloric acid to quench the reaction, 42 mL of CPME was added tothe solution, and the solution was washed once with 13 mL of 1 Nhydrochloric acid and three times with 13 mL of water. The organic layerwas concentrated under reduced pressure. The resulting residue wasdissolved in 42 mL of heptane, and the solution was washed byliquid-liquid extraction with 21 mL of DMF. To the resulting heptanelayer was added 21 mL of heptane, and the solution was washed byliquid-liquid extraction with 21 mL of acetonitrile. The washing step byliquid-liquid extraction with heptane and acetonitrile was repeated oncemore, and then the heptane layer was concentrated under reduced pressureto give a mixture containing TIPS9-Dpm-OH.

(3) The mixture obtained in the foregoing step was dissolved in 13.5 mLof THF, and 0.74 g of bis(p-nitrophenyl)phosphoryl azide (2.03 mmol) and0.30 mL of DBU (2.03 mmol) were added to the solution, followed bystirring at room temperature for 1 hour. The reaction solution wasdiluted with 39 mL of CPME, and the solution was washed by liquid-liquidextraction as follows: once with 13 mL of 5% sodium hydrogencarbonateaqueous solution and five times with 78 mL of water. The solution wasconcentrated under reduced pressure. The residue was dissolved in 27 mLof heptane, and the solution was washed by liquid-liquid extraction with14 mL of DMF. To the resultant heptane layer was added 14 mL of heptane,and the solution was washed by liquid-liquid extraction with 7 mL ofacetonitrile. The washing step by liquid-liquid extraction with heptaneand acetonitrile was repeated once more, then the heptane layer wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (heptane:ethyl acetate=30:1to 20:1) to give 0.42 g of TIPS9-Dpm-N₃ (yield: 24.4%, 2 steps).

¹H-NMR (400 MHz, Benzene-d₆) δ1.15-1.20 (m, 139H), 1.23-1.38 (m, 36H),1.50-1.82 (m, 12H), 2.16-2.26 (m, 6H), 3.56-3.70 (m, 4H), 3.73 (t, 2H),4.43 (s, 18H), 5.90 (s, 3H), 6.27 (s, 1H), 6.45 (dd, 1H), 6.57 (d, 1H),6.85-6.90 (m, 2H), 7.33-7.40 (m, 3H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.7 (27C), 13.7 (54C), 26.6 (3C), 26.7,26.9 (2C), 29.8-30.4 (18C), 38.3 (3C), 62.3 (9C), 62.8 (3C), 63.1, 68.3,68.4, 68.5, 100.6, 105.4, 115.0 (2C), 121.8, 129.4 (2C), 129.9, 132.8,158.2, 159.6, 161.2, 172.3 (3C)

(4) In 0.91 mL of THF, 0.35 g of TIPS9-Dpm-N₃ (0.14 mmol) was dissolved,and 0.11 g of triphenylphosphine (0.41 mmol) and 0.10 mL of water (5.50mmol) were added to the solution, followed by stirring at 60° C. for 6hours. The reaction solution was concentrated under reduced pressure.The residue was dissolved in 2.8 mL of heptane, and the solution waswashed by liquid-liquid extraction with 1.4 mL of DMF. The washing stepby liquid-liquid extraction with heptane and DMF was further repeatedtwice. Then, 1.4 mL of heptane was added to the heptane layer, and thesolution was washed by liquid-liquid extraction with 1.4 mL ofacetonitrile/water mixture (50/50). The washing step by liquid-liquidextraction with heptane and acetonitrile/water mixture (50/50) wasrepeated once more. To the resulting heptane layer was added 1.4 mL ofheptane, and the solution was washed by liquid-liquid extraction with1.4 mL of acetonitrile. The washing step by liquid-liquid extractionwith heptane and acetonitrile was repeated once more, then the heptanelayer was concentrated under reduced pressure, and the resulting residuewas purified by silica gel chromatography (heptane:ethyl acetate=17:1 toethyl acetate) to afford 0.25 g of TIPS9-Dpm-NH₂ (yield: 94.6%).

¹H-NMR (400 MHz, Benzene-d₆) δ1.15-1.20 (m, 189H), 1.23-1.38 (m, 36H),1.50-1.82 (m, 14H), 2.16-2.26 (m, 6H), 3.58-3.68 (m, 2H), 3.73 (t, 2H),3.79 (t, 2H), 4.43 (s, 18H), 5.62 (s, 1H), 5.90 (s, 3H), 6.53 (dd, 1H),6.60 (d, 1H), 6.93-6.99 (m, 2H), 7.52 (d, 1H), 7.55-7.61 (m, 2H)

¹³C-NMR (100 MHz, Benzene-d₆) δ12.7 (27C), 18.7 (54C), 26.6 (3C), 26.8,26.9 (2C), 29.8-30.4 (18C), 38.3 (3C), 53.9, 62.3 (9C), 62.8 (3C), 68.3(2C), 68.4, 100.7, 105.1, 114.7 (2C), 128.3, 128.9, 129.1 (2C), 139.0,158.0, 158.9, 160.2, 172.3 (3C)

Example 15

Synthesis of Fmoc-D-Ala-NH-(TIPS2-Dpm)

(Hereinafter, Fmoc-D-Ala-NH-(TIPS2-Dpm) represents the structure in theabove scheme.)

(1) In a mixed solution of 395 mL of THF (anhydrous) and 19.8 mL ofmethanol, 45.0 g of TIPS2-Dpm-C═O (51.9 mmol) was dissolved, and 2.36 gof sodium borohydride (62.3 mmol) was added to the solution, followed bystirring for 3 hours 30 minutes. To the reaction solution was added 49.3mL of 1 N hydrochloric acid to quench the reaction, 1125 mL of CPME wasadded to the solution, and the solution was washed twice with 340 mL of1 N hydrochloric acid and once with 340 mL of 20% sodium chlorideaqueous solution. To the organic layer was added 45.1 g of anhydrousmagnesium sulfate, and the mixture was stirred sufficiently, followed byfiltration. The filtrate was concentrated under reduced pressure to givea mixture containing TIPS2-Dpm-OH.

(2) The mixture obtained in the foregoing step was dissolved in 695 mLof toluene, and 19.3 g of Fmoc-D-Ala-NH₂ (62.3 mmol) and 168 μL ofmethanesulfonic acid (2.6 mmol) were added to the solution, followed bystirring at 100° C. for 1 hour. The reaction solution was cooled to 27°C., and 474 μL of DIPEA (2.7 mmol) was added to the solution to quenchthe reaction. The solution was diluted with 68 mL of CPME and 2250 mL ofheptane, and the solution was washed once by liquid-liquid extractionwith 2250 mL of a mixture of methanol/water=8/2. To the resultingorganic layer was added 68 mL of CPME, the solution was washed once byliquid-liquid extraction with 1125 mL of a mixture ofmethanol/water=8/2, and the organic layer was concentrated under reducedpressure. The resulting residue was dissolved in 180 mL of THF, and thesolution was concentrated under reduced pressure again. The residue wasdissolved in 113 mL of THF. To the solution was added 2251 mL ofmethanol, and the resulting precipitate was filtered. The precipitatewas further washed with 2251 mL of methanol, and the precipitate wasfiltered again. The precipitate was dried under reduced pressure toafford 48.8 g of Fmoc-D-Ala-NH-(TIPS2-Dpm) (yield: 81.0%, 2 steps).

¹H-NMR (400 MHz, CDCl₃) δ1.04-1.08 (m, 42H), 1.23-1.48 (m, 31H),1.49-1.59 (m, 4H), 1.67-1.80 (m, 4H), 3.67 (t, 4H), 3.82 (t, 2H), 3.89(t, 2H), 4.16 (t, 2H), 4.30 (t, 1H), 4.37-4.44 (m, 1H), 5.39 (d, 1H),6.10 (d, 1H), 6.65 (d, 1H), 6.78 (dd, 4H), 7.04-7.12 (m, 4H), 7.25-7.32(m, 2H), 7.39 (t, 2H), 7.55 (t, 2H), 7.76 (d, 2H)

¹³C-NMR (100 MHz, CDCl₃) δ 12.2 (6C), 18.2 (13C), 26.0 (2C), 26.2 (2C),29.4-29.8 (12C), 33.2 (2C), 47.2, 50.7, 56.1, 63.7 (2C), 67.3, 68.1,68.2, 114.7 (4C), 120.1 (2C), 125.2 (2C), 127.3 (2C), 127.9 (2C), 128.5(4C), 133.4, 133.5, 141.4 (2C), 143.8, 144.0, 156.2, 158.6 (2C), 171.1

Example 16

Synthesis of Fmoc-Cys(TIPS2-Dpm)-NH₂ and Deprotection

(Hereinafter, Fmoc-Cys(TIPS2-Dpm)-NH₂ represents the structure in theabove scheme.)

(1) In a mixed solution of 3.1 mL of THF (anhydrous) and 0.15 mL ofmethanol, 0.35 g of TIPS2-Dpm-C═O (0.40 mmol) was dissolved, and 18 mgof sodium borohydride (0.48 mmol) was added to the solution, followed bystirring for 3 hours. To the reaction solution was added 0.38 mL of 1 Nhydrochloric acid to quench the reaction, 8.7 mL of CPME was added tothe solution, and the solution was washed twice with 2.6 mL of 1 Nhydrochloric acid and once with 2.6 mL of 20% sodium chloride aqueoussolution. To the organic layer was added 0.35 g of anhydrous magnesiumsulfate, and the mixture was stirred sufficiently, followed byfiltration. The filtrate was concentrated under reduced pressure to givea mixture containing TIPS2-Dpm-OH.

(2) The mixture obtained in the foregoing step was dissolved in 5.4 mLof toluene, and 0.14 g of Fmoc-L-Csy-NH₂ (0.41 mmol) and 1.3 μL ofmethanesulfonic acid (0.02 mmol) were added to the solution, followed bystirring at 100° C. for 30 minutes. The reaction solution was cooled to5° C., and 3.7 μL of DIPEA (0.02 mmol) was added to the solution toquench the reaction. The solution was diluted with 0.5 mL of CPME and17.4 mL of heptane, and the solution was washed once by liquid-liquidextraction with 17.4 mL of a mixture of methanol/water=8/2. To theresulting organic layer was added 0.5 mL of CPME, the solution waswashed once by liquid-liquid extraction with 8.7 mL of a mixture ofmethanol/water=8/2, and the organic layer was concentrated under reducedpressure. The resulting residue was dissolved in 1.4 mL of THF, and thesolution was concentrated under reduced pressure again. To the residuewas added 17.5 mL of methanol, the mixture was cooled to 5° C., and thenthe solvent and the precipitate were separated by decantation. To theprecipitate was added 8.7 mL of methanol, the mixture was cooled to 5°C., and the solvent and the precipitate were separated by decantation.The precipitate was dried under reduced pressure to give 0.48 g ofFmoc-Cys(TIPS2-Dpm)-NH₂ (yield: 99.8%, 2 steps).

¹H-NMR (400 MHz, CDCl₃) δ1.03-1.09 (m, 42H), 1.24-1.48 (m, 28H),1.51-1.59 (m, 4H), 1.70-1.80 (m, 4H), 2.77 (d, 2H), 3.68 (t, 4H),3.85-3.94 (m, 4H), 4.22 (t, 1H), 4.26-4.34 (m, 1H), 4.45 (d, 2H), 5.17(s, 1H), 5.60 (s, 2H), 6.12 (s, 1H), 6.78-6.85 (m, 4H), 7.26-7.34 (m,6H), 7.41 (t, 2H), 7.56-7.64 (m, 2H), 7.78 (d, 2H)

¹³C-NMR (100 MHz, CDCl₃) δ12.2 (6C), 18.2 (12C), 26.0 (2C), 26.2 (2C),29.4-29.8 (12C), 33.2 (2C), 34.4, 47.3, 51.0, 53.5, 63.7 (2C), 67.3,68.1, 68.2, 114.6 (2C), 114.7 (2C), 120.2 (2C), 125.2 (2C), 127.3 (2C),127.9 (2C), 129.4 (2C), 129.5 (2C), 133.0 (2C), 141.5 (2C), 143.8 (2C),156.1, 158.5 (2C), 172.6

(3) In 5.34 mL of dichloromethane, 0.40 g of Fmoc-Cys(TIPS2-Dpm)-NH₂(0.34 mmol) was dissolved, and 0.34 mL of 3,6-dioxa-1,8-octanedithiol(2.07 mmol), 0.34 mL of triisopropylsilane (1.56 mmol), and 0.67 mL oftrifluoroacetic acid (8.81 mmol) were added to the solution, followed bystirring at room temperature for 20 minutes. After observingdisappearance of Fmoc-Cys(TIPS2-Dpm)-NH₂, the reaction solution wasconcentrated under reduced pressure. To 27 mL of diisopropyl ethercooled to 5° C. was added dropwise the residue, and the resultingprecipitate was filtered. This washing with diisopropyl ether andfiltration was further repeated three times. The resulting precipitatewas dried under reduced pressure to afford 0.090 g of Fmoc-L-Cys-NH₂.

¹H-NMR (400 MHz, DMSO-d₆) δ2.27 (t, 1H), 2.60-2.90 (m, 2H), 4.01-4.11(m, 1H), 4.18-4.38 (m, 3H), 7.15 (s, 1H), 7.33 (t, 2H), 7.37-7.52 (m,4H), 7.74 (dd, 2H), 7.89 (d, 2H)

¹³C-NMR (100 MHz, DMSO-d₆) δ26.2, 46.7, 57.1, 65.7, 120.1 (2C), 125.3(2C), 127.1 (2C), 127.6 (2C), 140.7 (2C), 143.8, 143.9, 156.0, 171.9

Example 17

Evaluation of Ability in Increasing Solubility of Peptide Compounds

Results of measurement of solubility of a compound protected with adiphenylmethane protective agent of the present invention are shown inFIG. 1.

Peptide used as model: H-Gly-Gly-Gly-NH₂

H-Gly-Gly-Gly-NH₂ and H-Gly-Gly-Gly-NH-(TIPS2-Dpm) were synthesized,CPME (cyclopentyl methyl ether) was saturated with each of the compoundsat 25° C., and the solubility was measured.

As a result, merely 0.039 mM of H-Gly-Gly-Gly-NH₂ to which a TIPS-typeprotective agent was not bonded was dissolved in CPME. On the otherhand, 426 mM of the peptide to which TIPS2-Dpm-NH₂ was bonded wasdissolved, that is, the compound led to about 10,000-fold or moreincrease in solubility. The results are shown in FIG. 1. The resultsdemonstrate that solubility of a peptide is significantly increased byderivatization using the diphenylmethane protective agent.H-Gly-Gly-Gly-NH₂ and H-Gly-Gly-Gly-NH-(TIPS2-Dpm) represent thefollowing structures.

Example 18

Synthesis of H-Gly-Gly-Gly-NH-(TIPS2-Dpm)

In 3.3 mL of CPME, 0.44 g of TIPS2-Dpm-NH₂ (0.50 mmol) was dissolved,and 0.8 mL of DMF, 0.43 mL of DIPEA (2.47 mmol), 0.27 g of Fmoc-Gly-OH(0.89 mmol), and 0.16 g of WSCI.HCl (0.84 mmol) were added to thesolution, followed by stirring at room temperature for 45 minutes. Afterobserving disappearance of TIPS2-Dpm-NH₂, 79 μL of2-(2-aminoethoxy)ethanol (0.79 mmol) was added to the solution, followedby stirring at room temperature for 15 minutes. To the reaction solutionwas added 0.32 g of sodium 3-mercapto-1-propanesulfonate (1.78 mmol)dissolved in 1.6 mL of DMSO, and 0.60 mL of DBU (4.01 mmol) was added tothe solution, followed by stirring for 30 minutes. After observingdisappearance of Fmoc-Gly-NH-(TIPS2-Dpm), the solution was cooled to 5°C., and then 1.59 mL of 4 M CPME/HCl (5.93 mmol) was added dropwise tothe solution. The solution was heated to room temperature, and 1.31 mLof CPME, 7.8 mL of 20% sodium chloride aqueous solution, and 6.7 mL of10% sodium carbonate aqueous solution were added to the solution, andthe solution was washed by liquid-liquid extraction. To the resultingorganic layer were added 9.7 mL of 20% sodium chloride aqueous solution,0.26 mL of DMSO, and 0.26 mL of DMF, and the solution was washed byliquid-liquid extraction. The solution was concentrated under reducedpressure, the residue was dissolved in 17.5 mL of heptane, and thesolution was washed twice by liquid-liquid extraction with 17.5 mL ofacetonitrile/water mixture (90/10). The heptane layer was concentratedunder reduced pressure, and the residue was dried under reduced pressureto give a mixture containing H-Gly-NH-(TIPS2-Dpm).Fmoc-Gly-NH-(TIPS2-Dpm) and H-Gly-NH-(TIPS2-Dpm) represent the followingstructures.

To the resulting mixture were added 3.2 mL of CPME, 0.8 mL of DMF, 0.42mL of DIPEA (2.41 mmol), 0.22 g of Fmoc-Gly-Gly-OH (0.63 mmol), and 0.25g of COMU (0.58 mmol), followed by stirring at room temperature for 1hour 15 minutes. After observing disappearance of H-Gly-NH-(TIPS2-Dpm),29 μL of 2-(2-aminoethoxy)ethanol (0.29 mmol) was added to the solution,followed by stirring at room temperature for 15 minutes. To the reactionsolution was added 0.22 g of sodium 3-mercapto-1-propanesulfonate (1.26mmol) dissolved in 1.2 mL of DMSO, and 0.49 mL of DBU (3.31 mmol) wasadded to the solution, followed by stirring for 30 minutes. Afterobserving disappearance of Fmoc-Gly-Gly-Gly-NH-(TIPS2-Dpm), the solutionwas cooled to 5° C., and then 1.23 mL of 4M CPME/HCl (4.85 mmol) wasadded dropwise to the solution. The solution was heated to roomtemperature, 1.34 mL of CPME, 6.4 mL of 20% sodium chloride aqueoussolution, and 5.6 mL of 10% sodium carbonate aqueous solution were addedto the solution, and the solution was washed by liquid-liquidextraction. To the resulting organic layer were added 4.2 mL of 50%dipotassium hydrogen phosphate aqueous solution, 0.11 mL of DMSO, and0.11 mL of DMF, and the solution was washed by liquid-liquid extraction.To the resulting organic layer were added 4.2 mL of 50% dipotassiumhydrogen phosphate aqueous solution, 0.11 mL of DMSO, and 0.11 mL ofDMF, and the solution was washed by liquid-liquid extraction. Thesolution was concentrated under reduced pressure, the residue wasdissolved in 17.9 mL of heptane, and the solution was washed byliquid-liquid extraction as follows: twice with 17.9 mL ofacetonitrile/water mixture (90/10), once with 17.9 mL of water, and oncewith 17.9 mL of acetonitrile/water mixture (90/10). The heptane layerwas concentrated under reduced pressure, and the residue was dried underreduced pressure to afford 0.36 g of H-Gly-Gly-Gly-NH-(TIPS2-Dpm). ESIMSMH+ 1039.9

Fmoc-Gly-Gly-Gly-NH-(TIPS2-Dpm) represents the following structure.

Example 19

Synthesis of H-Gly-Gly-Gly-NH₂

To 51.0 mg of H-Gly-Gly-Gly-NH-(TIPS2-Dpm) (0.049 mmol) were added 0.932mL of trifluoroacetic acid (12.17 mmol), 25 μL of3,6-dioxa-1,8-octanedithiol (0.151 mmol), and 25 μL oftriisopropylsilane (0.114 mmol), followed by stirring at roomtemperature for 2 hours. After observing disappearance ofH-Gly-Gly-Gly-NH-(TIPS2-Dpm), the reaction solution was concentratedunder reduced pressure. To 3.4 mL of diisopropyl ether cooled to 5° C.was added dropwise the residue, and the resulting precipitate wasfiltered. This wash sing with diisopropyl ether and filtration wasfurther repeated three times. The resulting precipitate was dried underreduced pressure to afford 14.8 mg of H-Gly-Gly-Gly-NH₂. ESIMS MK+ 226.9

The above results demonstrate that solubility in an organic solvent of acompound in which a functional group is protected using adiphenylmethane protective agent of the present invention issignificantly increased.

The invention claimed is:
 1. A method for protecting a functional group,comprising: reacting a protecting compound with a compound having afunctional group selected from the group consisting of a carboxy group,a hydroxy group, a diol group, an amino group, an amide group, and amercapto group, wherein the protecting compound is a diphenylmethanecompound represented by formula (1):

wherein, Y represents —OR¹⁹ wherein R¹⁹ represents a hydrogen atom or anactive ester-type protecting group, —NHR²⁰ wherein R²⁰ represents ahydrogen atom, a C₁₋₆ linear or branched alkyl group, or an aralkylgroup, an azide, a halogen atom, an oxime combined with a methylenegroup, or a carbonyl group combined with a methylene group, at least oneof R¹ to R¹⁰ represents a group represented by formula (2):—O—R¹¹—X-A  (2) and the others of R¹ to R¹⁰ each independently representa hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxygroup; R¹¹ represents a C₁₋₁₆ linear or branched alkylene group; Xrepresents O or CONR²¹ wherein R²¹ represents a hydrogen atom or a C₁₋₄alkyl group; and A represents a group represented by formula (3), (4),(5), (6), (7), (8), (9), (10), (11), (12), or (13):

wherein R¹², R¹³, and R¹⁴ may be the same or different and eachindependently represent a C₁₋₆ linear or branched alkyl group or anoptionally substituted aryl group; R¹⁵ represents a single bond or aC₁₋₃ linear or branched alkylene group; and R¹⁶, R¹⁷, and R¹⁸ eachindependently represent a C₁₋₃ linear or branched alkylene group, andwherein *--- represents a bonding to X.
 2. The method according to claim1, wherein the compound having the functional group is an amino acid ora peptide.
 3. The method according to claim 1, wherein Y is —OR¹⁹wherein R¹⁹ represents a hydrogen atom, —NHR²⁰ wherein R²⁰ represents ahydrogen atom, a C₁₋₆ linear or branched alkyl group, or an aralkylgroup, an azide, a halogen atom, an oxime combined with a methylenegroup, or a carbonyl group combined with a methylene group.
 4. Themethod according to claim 1, wherein Y is —OR¹⁹ wherein R¹⁹ represents ahydrogen atom or an active ester-type protecting group, —NHR²⁰ whereinR²⁰ represents a hydrogen atom, a C₁₋₆ linear or branched alkyl group,or an aralkyl group, an azide, a halogen atom, or an oxime combined witha methylene group.
 5. The method according to claim 1, wherein Y is—OR¹⁹ wherein R¹⁹ represents a hydrogen atom, —NHR²⁰ wherein R²⁰represents a hydrogen atom, a C₁₋₆ linear or branched alkyl group, or anaralkyl group, an azide, a halogen atom, or an oxime combined with amethylene group.
 6. The method according to claim 1, wherein at leastone of R¹ to R⁵ and at least one of R⁶ to R¹⁰ are each independently agroup represented by formula (2), and the others of R¹ to R⁵ and R⁶ toR¹⁰ are each independently a hydrogen atom, a C₁₋₄ alkyl group, or aC₁₋₄ alkoxy group.
 7. The method according to claim 1, wherein R¹¹ is aC₂₋₁₆ linear or branched alkylene group.
 8. The method according toclaim 1, wherein R¹¹ is a C₆₋₁₆ linear or branched alkylene group. 9.The method according to claim 1, wherein R¹⁵ is a single bond or amethylene group, and R¹⁶, R¹⁷, and R¹⁸ are each independently amethylene group.
 10. A peptide producing method in a liquid phase,comprising: reacting in a soluble solvent an amino acid or a peptide inwhich a functional group selected from the group consisting of a carboxygroup, a hydroxy group, a diol group, an amino group, an amide group,and a mercapto group is protected by a protecting compound with an aminoacid or a peptide in which a functional group which differs from theaforementioned functional group is protected, wherein the protectingcompound is a diphenylmethane compound represented by formula (1):

wherein, Y represents —OR¹⁹ wherein R¹⁹ represents a hydrogen atom or anactive ester-type protecting group, —NHR²⁰ wherein R²⁰ represents ahydrogen atom, a C₁₋₆ linear or branched alkyl group, or an aralkylgroup, an azide, a halogen atom, an oxime combined with a methylenegroup, or a carbonyl group combined with a methylene group, at least oneof R¹ to R¹⁰ represents a group represented by formula (2):—O—R¹¹—X-A  (2) and the others of R¹ to R¹⁰ each independently representa hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxygroup; R¹¹ represents a C₁₋₁₆ linear or branched alkylene group; Xrepresents O or CONR²¹ wherein R²¹ represents a hydrogen atom or a C₁₋₄alkyl group; and A represents a group represented by formula (3), (4),(5), (6), (7), (8), (9), (10), (11), (12), or (13):

wherein R¹², R¹³, and R¹⁴ may be the same or different and eachindependently represent a C₁₋₆ linear or branched alkyl group or anoptionally substituted aryl group; R¹⁵ represents a single bond or aC₁₋₃ linear or branched alkylene group; and R¹⁶, R¹⁷, and R¹⁸ eachindependently represent a C₁₋₃ linear or branched alkylene group, andwherein *--- represents a bonding to X.
 11. The method according toclaim 10, comprising the following steps (1) to (4): (1) condensing thediphenylmethane compound of formula (1) with the C-terminal carboxygroup of an N-protected amino acid or N-protected peptide in a solublesolvent to obtain an N-protected C-protected amino acid or N-protectedC-protected peptide in which the C-terminal is protected by thediphenylmethane compound of formula (1): (2) removing the protectinggroup on the N-terminal of the resulting N-protected C-protected aminoacid or N-protected C-protected peptide to obtain a C-protected aminoacid or C-protected peptide; (3) condensing an N-protected amino acid orN-protected peptide with the N-terminal of the resulting C-protectedamino acid or C-protected peptide to obtain an N-protected C-protectedpeptide; and (4) removing the protecting group on the N-terminal and theprotecting group on the C-terminal of the resulting N-protectedC-protected peptide to obtain a target peptide.
 12. The method accordingto claim 10, wherein Y is —OR¹⁹ wherein R¹⁹ represents a hydrogen atom,—NHR²⁰ wherein R²⁰ represents a hydrogen atom, a C₁₋₆ linear or branchedalkyl group, or an aralkyl group, an azide, a halogen atom, an oximecombined with a methylene group, or a carbonyl group combined with amethylene group.
 13. The method according to claim 10, wherein at leastone of R¹ to R⁵ and at least one of R⁶ to R¹⁰ are each independently agroup represented by formula (2), and the others of R¹ to R⁵ and R⁶ toR¹⁰ are each independently a hydrogen atom, a C₁₋₄ alkyl group, or aC₁₋₄ alkoxy group.
 14. The method according to claim 10, wherein R¹¹ isa C₂₋₁₆ linear or branched alkylene group.
 15. The method according toclaim 10, wherein R¹⁵ is a single bond or a methylene group, and R¹⁶,R¹⁷, and R¹⁸ are each independently a methylene group.
 16. A protectedamino acid or protected peptide, wherein a functional group selectedfrom the group consisting of a carboxy group, a hydroxy group, a diolgroup, an amino group, an amide group, and a mercapto group of an aminoacid or a peptide is protected by a protecting compound, and wherein theprotecting compound is a diphenylmethane compound represented by formula(1):

wherein, Y represents —OR¹⁹ wherein R¹⁹ represents a hydrogen atom or anactive ester-type protecting group, —NHR²⁰ wherein R²⁰ represents ahydrogen atom, a C₁₋₆ linear or branched alkyl group, or an aralkylgroup, an azide, a halogen atom, an oxime combined with a methylenegroup, or a carbonyl group combined with a methylene group, at least oneof R¹ to R¹⁰ represents a group represented by formula (2):—O—R¹¹—X-A  (2) and the others of R¹ to R¹⁰ each independently representa hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxygroup; R¹¹ represents a C₁₋₁₆ linear or branched alkylene group; Xrepresents O or CONR²¹ wherein R²¹ represents a hydrogen atom or a C₁₋₄alkyl group; and A represents a group represented by formula (3), (4),(5), (6), (7), (8), (9), (10), (11), (12), or (13):

wherein R¹², R¹³, and R¹⁴ may be the same or different and eachindependently represent a C₁₋₆ linear or branched alkyl group or anoptionally substituted aryl group; R¹⁵ represents a single bond or aC₁₋₃ linear or branched alkylene group; and R¹⁶, R¹⁷, and R¹⁸ eachindependently represent a C₁₋₃ linear or branched alkylene group, andwherein *--- represents a bonding to X.
 17. The protected amino acid orprotected peptide according to claim 16, wherein Y is —OR¹⁹ wherein R¹⁹represents a hydrogen atom, —NHR²⁰ wherein R²⁰ represents a hydrogenatom, a C₁₋₆ linear or branched alkyl group, or an aralkyl group, anazide, a halogen atom, an oxime combined with a methylene group, or acarbonyl group combined with a methylene group.
 18. The protected aminoacid or protected peptide according to claim 16, wherein at least one ofR¹ to R⁵ and at least one of R⁶ to R¹⁰ are each independently a grouprepresented by formula (2), and the others of R¹ to R⁵ and R⁶ to R¹⁰ areeach independently a hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxygroup.
 19. The protected amino acid or protected peptide according toclaim 16, wherein R¹¹ is a C₂₋₁₆ linear or branched alkylene group. 20.The protected amino acid or protected peptide according to claim 16,wherein R¹⁵ is a single bond or a methylene group, and R¹⁶, R¹⁷, and R¹⁸are each independently a methylene group.